Alkylenediamine derivatives

ABSTRACT

The present invention relates to alkylenediamine derivatives which relieve urinating contraction and therefore are of value as active ingredients of therapeutic agents for treating dysuria.

This is a 371 of PCT/JP95/00632 filed Mar. 31, 1995.

FIELD OF THE INVENTION

The present invention relates to a novel alkylenediamine derivativewhich shows a function to relieve urinating contraction and therefore isof value as an active ingredient of a therapeutic agent for treatingdysuria.

BACKGROUND OF THE INVENTION

Heretofore, flavoxate hydrochloride and oxybutynin hydrochloride whichdirectly function peripherally on urinary bladder have been used astherapeutic agents for treating dysuria. However, these compounds maygive certain side-effects to other organs such as digestive apparatus.

EP-0579169-A1 (Japanese Patent Provisional Publication H6-80645)describes an alkylenediamine of the formula (A): ##STR1## in which eachof R^(1A) and R^(2A) independently represents a phenyl, naphthyl oraromatic heterocyclic group which may have one to five same or differentsubstituents selected from the group consisting of alkyl, halogen,haloalkyl, hydroxyl, alkoxy, aryloxy, aralkyloxy, nitro, amino,alkylamino, aralkylamino, arylamino, acylamino, carboxyl,alkoxycarbonyl, aralkyloxycarbonyl, aryloxycarbonyl, amide, sulfo,alkoxysulfonyl, aralkyloxysulfonyl, aryloxysulfonyl, sulfonamide, and1H-tetrazol-5-yl; each of R^(3A) and R^(4A) independently representshydrogen, alkyl, aralkyl or aryl, otherwise R^(3A) and R^(4A) arecombined in conjunction with the nitrogen atom to which R^(3A) andR^(4A) are attached to form 5 to 7 membered ring which may containoxygen, sulfur or nitrogen and which may have a substituent selectedfrom the group consisting of alkyl, aralkyl, phenyl, hydroxyl, alkoxy,carboxyl, alkoxycarbonyl, aralkyloxycarbonyl, aryloxycarbonyl, andamide; X^(A) represents oxygen, sulfur or imino; A represents oxygen orsulfur; Z^(A) represents --CH₂ --, --CO--, or --CS--; m^(A) is aninteger of 0 to 4; n^(A) is an integer of 0 to 4; each of p^(A) andq^(A) independently is an integer of 0 to 5 under the condition that thetotal of p^(A) and q^(A) is in the range of 1 to 5, or itspharmacologically acceptable salt is of value as an active ingredient ofa therapeutic agent for treating dysuria, because the compound canrelieve urinating contraction which is observed under high intracysticpressure, and therefore is employable for treating nervous dysuria,chronic prostatitis, chronic cystitis, dysuria caused by neurogenicbladder or unstable bladder, incontinence of urine, urgency ofmicturition, and residual urine.

The object of the invention is to provide a novel alkylenediaminederivative showing a function to relieve urinating contraction which isobserved under high intracystic pressure.

DISCLOSURE OF THE INVENTION

The present invention resides in an alkylenediamine derivative ofbenzothiazine type which is represented by the formula (1): ##STR2## inwhich

R¹ represents an atom or a group selected from the group consisting ofhydrogen, alkyl having 1-8 carbon atoms, halogen, haloalkyl having 1-4carbon atoms, hydroxyl, alkoxy having 1-8 carbon atoms, aryloxy having4-10 carbon atoms, aralkyloxy having 5-14 carbon atoms (its alkylportion has 1-4 carbon atoms), nitro, amino, cyano, alkylamino having1-8 carbon atoms, aralkylamino having 5-14 carbon atoms (its alkylportion has 1-4 carbon atoms), arylamino having 4-10 carbon atoms,aliphatic acylamino having 1-8 carbon atoms, carboxyl, alkoxycarbonylhaving 2-9 carbon atoms, aralkyloxycarbonyl having 6-15 carbon atoms(its alkyl portion has 1-4 carbon atoms), aryloxycarbonyl having 5-11carbon atoms, carbamoyl, sulfo, alkoxysulfonyl having 1-8 carbon atoms,aralkyloxysulfonyl having 5-14 carbon atoms (its alkyl portion has 1-4carbon atoms), aryloxysulfonyl having 4-10 carbon atoms, sulfonamide,and 1H-tetrazol-5-yl;

R² represents hydrogen, hydroxyl, alkyl having 1-8 carbon atoms, alkenylhaving 2-9 carbon atoms, alkoxy having 1-8 carbon atoms, or an arylhaving 4-10 carbon atoms, aralkyl having 5-14 carbon atoms (its alkylportion has 1-4 carbon atoms) or aromatic heterocyclic group which mayhave one to five same or different substituents selected from the groupconsisting of alkyl having 1-8 carbon atoms, halogen, haloalkyl having1-4 carbon atoms, hydroxyl, alkoxy having 1-8 carbon atoms, aryloxyhaving 4-10 carbon atoms, aralkyloxy having 5-14 carbon atoms (its alkylportion has 1-4 carbon atoms), nitro, amino, cyano, alkylamino having1-8 carbon atoms, aralkylamino having 5-14 carbon atoms (its alkylportion has 1-4 carbon atoms), arylamino having 4-10 carbon atoms,aliphatic acylamino having 1-8 carbon atoms, carboxyl, alkoxycarbonylhaving 2-9 carbon atoms, aralkyloxycarbonyl having 6-15 carbon atoms(its alkyl portion has 1-4 carbon atoms), aryloxycarbonyl having 5-11carbon atoms, carbamoyl, sulfo, alkoxysulfonyl having 1-8 carbon atoms,aralkyloxysulfonyl having 5-14 carbon atoms (its alkyl portion has 1-4carbon atoms), aryloxysulfonyl having 4-10 carbon atoms, sulfonamide and1H-tetrazol-5-yl;

each of R³ and R⁴ independently represents hydrogen, alkyl having 1-8carbon atoms, aralkyl having 5-14 carbon atoms (its alkyl portion has1-4 carbon atoms), or aryl having 4-10 carbon atoms, or R³ and R⁴ formin combination with the nitrogen atom to which R³ and R⁴ are attached, ahetero ring which may contain another nitrogen, oxygen or sulfur as thering-forming atom in addition to the former nitrogen atom;

k is an integer of 1 to 4;

each of m and n independently represents an integer of 0 to 4, under thecondition that the total number of m and n is in the range of 0 to 4;

p is 0, 1 or 2;

q is 0 or 1; and

each of w, x, y and z independently is an integer of 0 to 2, under thecondition that the total number of w, x, y and z is 1 or 2.

Among the alkylenediamine derivatives of benzothiazine type representedby the above-mentioned formula (1), preferred is an alkylenediaminederivative having the following formula (2): ##STR3## in which R¹, R²,R³, R⁴, k, m, and n are the same as those defined for the formula (1).

Among the alkylenediamine derivatives of benzothiazine type representedby the above-mentioned formula (1), also preferred is an alkylenediaminederivative having the following formula (3): ##STR4## in which R¹, R²,R³, R⁴, k, m, and n are the same as those defined for the formula (1).

The alkylenediamine derivative of the formula (1) entirely differs fromthe alkylenediamine derivative of the aforementioned EP-0579169-A1 inthat the former has on one end a condensed heterocyclic ring containingsulfur and nitrogen atoms.

The present invention further provides an alkylenediamine derivative ofsaccharin type having the formula (I): ##STR5## in which

R¹ represents an atom or a group selected from the group consisting ofhydrogen, alkyl having 1-8 carbon atoms, halogen, haloalkyl having 1-4carbon atoms, hydroxyl, alkoxy having 1-8 carbon atoms, aryloxy having4-10 carbon atoms, aralkyloxy having 5-14 carbon atoms (its alkylportion has 1-4 carbon atoms), nitro, amino, cyano, alkylamino having1-8 carbon atoms, aralkylamino having 5-14 carbon atoms (its alkylportion has 1-4 carbon atoms), arylamino having 4-10 carbon atoms,aliphatic acylamino having 1-8 carbon atoms, carboxyl, alkoxycarbonylhaving 2-9 carbon atoms, aralkyloxycarbonyl having 6-15 carbon atoms(its alkyl portion has 1-4 carbon atoms), aryloxycarbonyl having 5-11carbon atoms, carbamoyl, sulfo, alkoxysulfonyl having 1-8 carbon atoms,aralkyloxysulfonyl having 5-14 carbon atoms (its alkyl portion has 1-4carbon atoms), aryloxysulfonyl having 4-10 carbon atoms, sulfonamide,and 1H-tetrazol-5-yl;

R² represents phenyl, naphthyl or aromatic heterocyclic group which mayhave one to five same or different substituents selected from the groupconsisting of alkyl having 1-8 carbon atoms, halogen, haloalkyl having1-4 carbon atoms, hydroxyl, alkoxy having 1-8 carbon atoms, aryloxyhaving 4-10 carbon atoms, aralkyloxy having 5-14 carbon atoms (its alkylportion has 1-4 carbon atoms), nitro, amino, cyano, alkylamino having1-8 carbon atoms, aralkylamino having 5-14 carbon atoms (its alkylportion has 1-4 carbon atoms), arylamino having 4-10 carbon atoms,aliphatic acylamino having 1-8 carbon atoms, carboxyl, alkoxycarbonylhaving 2-9 carbon atoms, aralkyloxycarbonyl having 6-15 carbon atoms(its alkyl portion has 1-4 carbon atoms), aryloxycarbonyl having 5-11carbon atoms, carbamoyl, sulfo, alkoxysulfonyl having 1-8 carbon atoms,aralkyloxysulfonyl having 5-14 carbon atoms (its alkyl portion has 1-4carbon atoms), aryloxysulfonyl having 4-10 carbon atoms, sulfonamide and1H-tetrazol-5-yl;

each of R³ and R⁴ independently represents hydrogen, alkyl having 1-8carbon atoms, aralkyl having 5-14 carbon atoms (its alkyl portion has1-4 carbon atoms), or aryl having 4-10 carbon atoms, or R³ and R⁴ formin combination with the nitrogen atom to which R³ and R⁴ are attached, afive to seven membered hetero ring having the formula (II): ##STR6##

in which Z is a group of the formula (III): ##STR7##

in which R⁵ represents hydrogen or a group selected from the groupconsisting of alkyl having 1-8 carbon atoms, aralkyl having 5-14 carbonatoms (its alkyl portion has 1-4 carbon atoms), phenyl, 2-pyrimidinyl,carboxyl, alkoxycarbonyl having 2-9 carbon atoms, aralkyl-oxycarbonylhaving 6-15 carbon atoms (its alkyl portion has 1-4 carbon atoms), andaryloxycarbonyl having 5-11 carbon atoms,

--O--, --S--, --SO--, or --SO₂ --, and t is 0 or 1;

in which the five to seven hetero ring may have 1 to 5 substituentsselected from the group consisting of alkyl having 1-5 carbon atoms,aralkyl having 5-14 carbon atoms (its alkyl has 1-4 carbon atoms),phenyl, hydroxyl, alkoxy having 1-8 carbon atoms, carboxyl,alkoxycarbonyl having 2-9 carbon atoms, aralkyloxycarbonyl having 6-15carbon atoms (its alkyl has 1-4 carbon atoms), aryloxycarbonyl having5-11 carbon atoms, aliphatic acyl having 1-8 carbon atoms, aromatic acylhaving 5-11 carbon atoms, and carbamoyl;

m represents an integer of 1 to 4, and n represents an integer of 0 to4;

each of p and q independently represents an integer of 0 to 5, under thecondition that the total number of p and q is in the range of 1 to 5;

x is 0, 1 or 2; and

y is 0 or 1.

Among the alkylenediamine derivatives of saccharin type represented bythe above-mentioned formula (I), preferred is an alkylenediaminederivative having the following formula (IV): ##STR8## in which R¹, R²,R³, R⁴, m, n, p and q are the same as those defined for the formula (I).

Among the alkylenediamine derivatives of saccharin type represented bythe above-mentioned formula (I), also preferred is an alkylenediaminederivative having the following formula (V): ##STR9## in which R¹, R²,R³, R⁴, m, n, p and q are the same as those defined for the formula (I).

Among the alkylenediamine derivatives of saccharin type represented bythe above-mentioned formula (I), also preferred is an alkylenediaminederivative having the following formula (VI): ##STR10## in which R¹, R²,R³, R⁴ m, n, p and q are the same as those defined for the formula (I).

The alkylenediamine derivative of the formula (I) entirely differs fromthe alkylenediamine derivative of the aforementioned EP-0579169-A1 inthat the former has on one end a benzisothiazoline structure.

PREFERRED EMBODIMENTS OF THE INVENTION

In the formula (1), the halogen represented by R¹ preferably isfluorine, chlorine or bromine, and chlorine is most preferred. The alkylhaving 1-8 carbon atoms which is represented by R¹ preferably is methyl,ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, hexyl, heptyl, oroctyl. The haloalkyl having 1-4 carbon atoms preferably istrifluoromethyl, chloromethyl, or fluoromethyl. The alkoxy having 1-8carbon atoms preferably is methoxy, ethoxy, or propoxy. The aryloxyhaving 4-10 carbon atoms (which may have nucleus substituents such ashalogen, cyano, alkyl, alkoxy, amino, or alkoxycarbonyl) preferably isphenoxy or p-chlorophenoxy. The aralkyloxy having 5-14 carbon atoms (itsalkyl portion has 1-4 carbon atoms) preferably is benzyloxy,pyridylmethyloxy, naphthylmethyloxy, or thenyloxy. The alkylamino having1-8 carbon atoms preferably methylamino, dimethylamino, ethylamino,propylamino, or isobutylamino. The aralkylamino having 5-14 carbon atoms(its alkyl portion has 1-4 carbon atoms, and which may have nucleussubstituents such as halogen, cyano, alkyl, alkoxy, amino, oralkoxycarbonyl) preferably is benzylamino or(4-chlorophenyl)methylamino. The arylamino having 4-10 carbon atoms(which may have nucleus substituents such as halogen, cyano, alkyl,alkoxy, amino, or alkoxycarbonyl) preferably is phenylamino orp-chlorophenylamino. The aliphatic acylamino having 1-8 carbon atompreferably is acetylamino or propionylamino. The alkoxycarbonyl having2-9 carbon atoms preferably is methoxycarbonyl, ethoxycarbonyl, orpropoxycarbonyl. The aralkyloxycarbonyl having 6-15 carbon atoms (itsalkyl portion has 1-4 carbon atoms) preferably is benzyloxycarbonyl,pyridylmethyloxycarbonyl, naphthylmethyloxycarbonyl, orthenyloxycarbonyl. The aryloxycarbonyl having 5-11 carbon atomspreferably is phenoxycarbonyl, naphthyloxycarbonyl, orthienyloxycarbonyl. The alkoxysulfonyl having 1-8 carbon atomspreferably is methoxysulfonyl or ethoxysulfonyl. The aralkyloxysulfonylhaving 5-14 carbon atoms (its alkyl portion has 1-4 carbon atoms)preferably is benzyloxysulfonyl, naphthylmethyloxysulfonyl, orthenyloxysulfonyl. The aryloxysulfonyl having 4-10 carbon atomspreferably is phenoxysulfonyl, naphthyloxysulfonyl, orthienyloxysulfonyl.

In the formula (1), particularly preferred for R¹ is hydrogen, halogen,alkyl having 1-8 carbon atoms, or alkoxy having 1-8 carbon atoms.

In the formula (1), R² represents hydrogen, hydroxyl, alkyl having 1-8carbon atoms, alkenyl having 2-9 carbon atoms, alkoxy having 1-8 carbonatoms, or aryl having 4-10 carbon atoms, aralkyl having 5-14 carbonatoms (its alkyl portion has 1-4 carbon atoms), or aromatic heterocyclicgroup which may have one to five same or different substituents. Thealkyl having 1-8 carbon atoms which is represented by R² preferably ismethyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, hexyl,heptyl, or octyl. The alkenyl having 2-9 carbon atoms preferably isallyl, 1-propenyl, 2-methyl-2-propenyl, 2-methyl-1-propenyl, 1-butenyl,2-butenyl, 3-butenyl, 3-methyl-3-butenyl, 3-methyl-2-butenyl,4-pentenyl, 4-methyl-4-pentenyl, 4-methyl-3-pentenyl, 5-hexenyl,5-methyl-5-hexenyl, 5-methyl-4-hexenyl, 6-heptenyl, 6-methyl-6-heptenyl,6-methyl-5-heptenyl, 7-octenyl, 7-methyl-7-octenyl, or7-methyl-6-octenyl. The alkoxy having 1-8 carbon atoms preferably ismethoxy, ethoxy, or propoxy. The aryl having 4-10 carbon atomspreferably is phenyl or naphthyl. The aralkyl having 5-14 carbon atoms(its alkyl portion has 1-4 carbon atoms) preferably is benzyl ornaphthylmethyl. The aromatic hetero ring preferably is furan ring,thiophene ring, pyridine ring, quinoline ring, or indole ring.

The halogen which may be attached to the above-mentioned aryl, aralkylor aromatic heterocyclic group preferably is fluorine, chlorine, orbromine. The alkyl having 1-8 carbon atoms preferably is methyl, ethyl,propyl, isopropyl, butyl, isobutyl, pentyl, hexyl, heptyl, or octyl. Thehaloalkyl having 1-4 carbon atoms preferably is trifluoromethyl,chloromethyl, or fluoromethyl. The alkoxy having 1-8 carbon atomspreferably is methoxy, ethoxy, or propoxy. The aryloxy having 4-10carbon atoms (which may have nucleus substituents such as halogen,cyano, alkyl, alkoxy, amino, or alkoxycarbonyl) preferably is phenoxy orp-chlorophenoxy. The aralkyloxy having 5-14 carbon atoms (its alkylportion has 1-4 carbon atoms) preferably is benzyloxy, pyridylmethyloxy,naphthylmethyloxy, or thenyloxy. The alkylamino having 1-8 carbon atomspreferably is methylamino, dimethylamino, ethylamino, propylamino, orisobutylamino. The aralkylamino having 5-14 carbon atoms (its alkylportion has 1-4 carbon atoms, and which may have nucleus substituentssuch as halogen, cyano, alkyl, alkoxy, amino, or alkoxycarbonyl)preferably is benzylamino or (4-chlorophenyl)methylamino. The arylaminohaving 4-10 carbon atoms (which may have nucleus substituents such ashalogen, cyano, alkyl, alkoxy, amino, or alkoxycarbonyl) preferably isphenylamino or p-chlorophenylamino. The aliphatic acylamino having 1-8carbon atom preferably is acetylamino or propionylamino. Thealkoxycarbonyl having 2-9 carbon atoms preferably is methoxycarbonyl,ethoxycarbonyl, or propoxycarbonyl. The aralkyloxycarbonyl having 6-15carbon atoms (its alkyl portion has 1-4 carbon atoms) preferably isbenzyloxycarbonyl, pyridylmethyloxycarbonyl, naphthylmethyloxycarbonyl,or thenyloxycarbonyl. The aryloxycarbonyl having 5-11 carbon atomspreferably is phenoxycarbonyl, pyridyloxycarbonyl, naphthyloxycarbonyl,or thienyloxycarbonyl. The alkoxysulfonyl having 1-8 carbon atomspreferably is methoxysulfonyl or ethoxysulfonyl. The aralkyloxysulfonylhaving 5-14 carbon atoms (its alkyl portion has 1-4 carbon atoms)preferably is benzyloxysulfonyl, naphthylmethyloxysulfonyl, orthenyloxysulfonyl. The aryloxysulfonyl having 4-10 carbon atomspreferably is phenoxysulfonyl, naphthyloxysulfonyl, orthienyloxysulfonyl.

Particularly preferred for R² is hydrogen, alkyl having 1-8 carbonatoms, alkoxy having 1-8 carbon atoms, hydroxyl, or phenyl, furyl,thienyl or pyridyl which has no substituents, or phenyl having, assubstituent, halogen, alkyl having 1-8 carbon atoms, or alkoxy having1-8 carbon atoms.

In the formula (1), the alkyl having 1-8 carbon atoms which isrepresented by R³ or R⁴ preferably is methyl, ethyl, propyl, isopropyl,butyl, or isobutyl. The aralkyl having 5-14 carbon atoms (its alkylportion has 1-4 carbon atoms) preferably is benzyl, phenylethyl, orphenylpropyl. The aryl having 4-10 carbon atoms preferably is phenyl,pyridyl, or naphthyl.

The heterocyclic group which is formed by the combination of R³ and R⁴and the nitrogen atom to which R³ and R⁴ are attached and which mayfurther have nitrogen, oxygen, or sulfur as the ring member preferablyis a five to seven membered heterocyclic group having the formula (4):##STR11## in which Z is a group of the formula (5): ##STR12## in whichR⁵ represents hydrogen, or a group selected from the group consisting ofalkyl having 1-8 carbon atoms, aralkyl having 5-14 carbon atoms (itsalkyl portion has 1-4 carbon atoms), phenyl, 2-pyrimidinyl, carboxyl,alkoxycarbonyl having 2-9 carbon atoms, aralkyloxycarbonyl having 6-15carbon atoms (its alkyl portion has 1-4 carbon atoms), andaryloxycarbonyl having 5-11 carbon atoms!, --O--, --S--, --SO--, or--SO₂ --, and t is 0 or 1, or 1,2,3,4-tetrahydroisoquinoline group, or2,3-dihydro-1H-benz de!isoquinoline group.

The five to seven membered heterocyclic group represented by the formula(4) preferably is morpholino, piperidino, homomorpholino,1-pyrrolidinyl, thiomorpholino, 1-piperazinyl, perhydroazepin-1-yl,S-oxythiomorpholino, or S,S-dioxythiomorpholino.

The alkyl having 1-8 carbon atoms which is represented by R⁵ of theformula (5) for Z of the formula (4) preferably is methyl, ethyl,propyl, isopropyl, butyl, or isobutyl. The aralkyl having 5-14 carbonatoms (its alkyl has 1-4 carbon atoms) preferably is benzyl,phenylethyl, or phenylpropyl. The alkoxycarbonyl having 2-9 carbon atomspreferably is methoxycarbonyl, ethoxycarbonyl, or propoxycarbonyl. Thearalkyloxycarbonyl having 6-15 carbon atoms (its alkyl portion has 1-4carbon atoms) preferably is benzyloxycarbonyl, pyridylmethyloxycarbonyl,naphthylmethyloxycarbonyl, or thenyloxycarbonyl. The aryloxycarbonylhaving 5-11 carbon atoms preferably is phenoxycarbonyl,naphthyloxycarbonyl, or thienyloxycarbonyl.

The five to seven membered heterocyclic group of the formula (4),1,2,3,4-tetrahydroisoquinoline group, or 2,3-dihydro-1H-benzde!isoquinoline group may have 1 to 5 substituents selected from thegroup consisting of alkyl having 1-8 carbon atoms which may have one ortwo substituents such as aryl having 4-10 carbon atoms (which may besubstituted with halogen, alkyl having 1-5 carbon atoms, alkoxy having1-5 carbon atoms, or aliphatic acyl having 1-5 carbon atoms), phenyl,hydroxyl, alkoxy having 1-8 carbon atoms which may have one or twosubstituents such as aryl having 4-10 carbon atoms (which may besubstituted with halogen, alkyl having 1-5 carbon atoms, alkoxy having1-5 carbon atoms, or aliphatic acyl having 1-5 carbon atoms), aryloxyhaving 4-10 carbon atoms, aralkylthio having 5-14 carbon atoms (itsalkyl portion has 1-4 carbon atoms), arylthio having 4-10 carbon atoms,carboxyl, alkoxycarbonyl having 2-9 carbon atoms, aralkyloxycarbonylhaving 6-15 carbon atoms (its alkyl portion has 1-4 carbon atoms),aryloxycarbonyl having 5-11 carbon atoms, aliphatic acyl having 1-8carbon atoms, aromatic acyl having 5-11 carbon atoms, cyano, andcarbamoyl.

Among the above-mentioned substituents, the alkyl having 1-5 carbonatoms preferably is methyl, ethyl, propyl, isopropyl, butyl, orisobutyl. The alkyl having 1-8 carbon atoms which may have one or twosubstituted or unsubstituted aryl having 4-10 carbon atoms preferably isbenzyl, phenylethyl, phenylpropyl, diphenylmethyl, chlorobenzyl,methylbenzyl, methoxybenzyl, acetylbenzyl, or thienylmethyl. The alkoxyhaving 1-8 carbon atoms which may have one or two substituted orunsubstituted aryl having 4-10 carbon atoms preferably is methoxy,ethoxy, propoxy, benzyloxy, diphenylmethyloxy, phenylethyloxy,chlorobenzyloxy, methylbenzyloxy, methoxybenzyloxy, acetylbenzyloxy,2-thienylmethyloxy, naphthylmethyloxy, 2-pyridylmethyloxy,chloronaphthylmethyloxy, dichlorobenzyloxy, ordi(chlorophenyl)methyloxy. The aryloxy having 4-10 carbon atomspreferably is phenoxy, chlorophenoxy, 3-thienyloxy, methoxyphenoxy,methylphenoxy, acetylphenoxy, dichlorophenoxy, naphthyloxy,chloronaphthyloxy, or 4-pyridyloxy. The aralkylthio having 5-14 carbonatoms (its alkyl portion has 1-4 carbon atoms) preferably is benzylthio,phenylethylthio, chlorobenzylthio, methylbenzylthio, methoxybenzylthio,acetylbenzylthio, 2-thienylmethylthio, naphthylmethylthio,2-pyridylmethylthio, chloronaphthylmethylthio, dichlorobenzylthio, ordi(chlorophenyl)methylthio. The arylthio having 4-10 carbon atomspreferably is phenylthio, 3-thienylthio, methoxyphenylthio,methylphenylthio, acetylphenylthio, dichlorophenylthio, naphthylthio,chloronaphthylthio, or 4-pyridylthio. The alkoxycarbonyl having 2-9carbon atoms preferably is methoxycarbonyl, ethoxycarbonyl, orpropoxycarbonyl. The aralkyloxycarbonyl having 6-15 carbon atoms (itsalkyl portion has 1-4 carbon atoms) preferably is benzyloxycarbonyl,pyridylmethyloxycarbonyl, naphthylmethyloxycarbonyl, orthenyloxycarbonyl. The aryloxycarbonyl having 5-11 carbon atomspreferably is phenoxycarbonyl, naphthyloxycarbonyl, orthienyloxycarbonyl. The aliphatic acyl having 1-8 carbon atomspreferably is formyl, acetyl, or propionyl. The aromatic acyl having5-11 carbon atoms preferably is benzoyl or phthaloyl. If the two or moresubstituents are attached, these substituents may be the same ordifferent.

The five to seven membered heterocyclic group represented by the formula(4) preferably is morpholino, piperidino, homomorpholino,1-pyrrolidinyl, thiomorpholino, 1-piperazinyl, perhydroazepin-1-yl,S-oxythiomorpholino, or S,S-dioxythiomorpholino. The heterocyclic groupmay not have substituents, or may have substituents such as alkyl having1-8 carbon atoms, alkyl having 1-8 carbon atoms which have one or twophenyl groups, phenyl, thienyl, acyl having 1-8 carbon atoms, carbamoyl,or 2-pyrimidinyl on its carbon or nitrogen atom.

In the formula (1), k preferably is 1 or 2, and 1 is most preferred. mpreferably is 0. n preferably is 1, 2, or 3. The alkylenediaminederivative of the formula (1) in which p, q, w, x, y and z are 2, 1, 0,0, 1 and 0, respectively, corresponds to the alkylenediamine derivativeof the formula (2). The alkylenediamine derivative of the formula (1) inwhich p, q, w, x, y and z are 2, 1, 1, 0, 0 and 0, respectively,corresponds to the alkylenediamine derivative of the formula (3). In theformula (1), if q is o, two hydrogen atoms are attached.

The alkylenediamine derivative derivative of the formula (1) can besynthesized utilizing reactions which are known in the technical fieldof organic chemistry.

For instance, the alkylenediamine of the formula (2) can be prepared byreacting a ketal compound having the formula (6): ##STR13## in which R¹and k have the same meanings as defined in the formula (1)

with a compound having the formula (7): ##STR14## in which R², R³, R⁴, mand n have the same meanings as defined in the formula (1), and Q is areleasable group such as halogen, tosyloxy, or mesyloxy, to give anethylene ketal compound, and then subjecting the resulting compound tode-ketal reaction.

In the above-mentioned preparation process, the ketal compound of theformula (6) and the compound of the formula (7) are caused to react at atemperature from room temperature to the reflux temperature for 1 to 50hours, in an organic solvent such as acetone, dimethylformamide, methylethyl ketone, isobutyl methyl ketone, isopropyl alcohol, ethanol, ordimethoxyethane, in the presence of a base such as potassium carbonate,sodium carbonate, cesium carbonate, sodium hydrogen carbonate, sodiumhydride, sodium metal, sodium ethoxide, or sodium hydroxide, to preparean ethylene ketal compound corresponding to the compound of the formula(2). In the reaction, 1 to 2 moles of the compound of the formula (7)and the 2 to 8 moles of the base are preferably employed per one mole ofthe compound of the formula (6). Subsequently, the ethylene ketal issubjected to the reaction for removing the ketal by treating withdiluted hydrochloric acid, diluted hydrochloric acid/methanol mixture,diluted hydrochloric acid/tetrahydrofuran mixture, diluted hydrochloricacid/ethnaol mixture, sulfuric acid/acetone mixture, p-toluenesulfonicacid/acetone mixture, 80% acetic acid, silica gel/water/dichloromethanemixture, oxalic acid/water/dichloromethane mixture, sulfuricacid/water/dichloromethane mixture, or triphenylmethyltetrafluoroborate/dichloromethane mixture, to give the alkylenediaminederivative of the formula (2).

Alternatively, the alkylenediamine derivative of the formula (2) can beprepared by reacting a ketal compound of the formula (8): ##STR15## inwhich R¹, R², k, m and n have the same meanings as defined in theformula (1), and Q is a releasable group such as halogen, tosyloxy, ormesyloxy, with a compound having the formula (9): ##STR16## in which R³and R⁴ have the same meanings as defined in the formula (1),

to give an ethylene ketal compound, and then subjecting the resultingcompound to de-ketal reaction.

In the above-mentioned preparation process, the ketal compound of theformula (8) and the compound of the formula (9) are caused to react at50° to 150° C. for 1 to 2 hours, generally, in the absence of a solvent,to give an ethylene ketal compound which corresponds to the compound ofthe formula (2). The ethylene ketal compound is then subjected to areaction for removal of ketal structure in the same manner as above, togive the alkylenediamine derivative of the formula (2).

In the reaction, 1 to 2 moles of the compound of the formula (9) ispreferably employed per one mole of the compound of the formula (8).

A compound of the formula (1) in which p is 0 or 1, or q is 0, which issimilar to the compound of the formula (2) can be synthesized in amanner similar to the above-mentioned process.

The alkylenediamine derivative of the formula (3) can be prepared byreacting a compound of the formula (10): ##STR17## in which R¹ and khave the same meanings as defined in the formula (1)

with a compound of the aformementioned formula (7).

In the above-mentioned preparation process, the compound of the formula(10) and the compound of the formula (7) are caused to react at atemperature from room temperature to the reflux temperature for 1 to 50hours, in an organic solvent such as acetone, dimethylformamide, methylethyl ketone, isobutyl methyl ketone, isopropyl alcohol, ethanol, ordimethoxyethane, in the presence of a base such as potassium carbonate,sodium carbonate, cesium carbonate, sodium hydrogen carbonate, sodiumhydride, metallic sodium, sodium ethoxide, or sodium hydroxide, toprepare an ethylene ketal compound corresponding to the compound of theformula (3). In the reaction, 1 to 2 moles of the compound of theformula (7) and the 2 to 8 moles of the base are preferably employed perone mole of the compound of the formula (10).

Alternatively, the alkylenediamine derivative of the formula (3) can beprepared by reacting a compound of the formula (11): ##STR18## in whichR¹, R², k, m and n have the same meanings as defined in the formula (1),and Q is a releasable group as mentioned above,

with a compound having the aforementioned formula (9).

In the above-mentioned preparation process, the compound of the formula(11) and the compound of the formula (9) are caused to react at 50° to150° C. for 1 to 20 hours, generally, in the absence of a solvent, togive the compound of the formula (3). If necessary, a solvent which doesnot participate in the reaction can be employed.

A compound of the formula (1) in which p is 0 or 1, or q is 0, which issimilar to the compound of the formula (3) can be synthesized in amanner similar to the above-mentioned process.

Further, a compound having the formula (12): ##STR19## in which R¹ and khave the same meanings as defined in the formula (1)

can be caused to react with the compound of the formula (7), to give analkylenediamine derivative having the formula (13): ##STR20## in whichR¹, R², R³, R⁴, k, m, and n have the same meanings as defiend in theformula (1),

which belongs to the alkylenediamine derivative of the formula (1).

Furthermore, a compound having the formula (14): ##STR21## in which R¹and k have the same meanings as defined in the formula (1)

can be caused to react with the compound of the formula (7), to give analkylenediamine derivative having the formula (15): ##STR22## in whichR¹, R², R³, R⁴, k, m, and n have the same meanings as defiend in theformula (1),

which belongs to the alkylenediamine derivative of the formula (1).

The reaction conditions for preparing the alkylenediamine derivative ofthe formula (13) and the alkylenediamine derivative of the formula (15)are almost the same as those adopted for the preparation of thealkylenediamine derivative of the formula (3) starting from the thecompound of the formula (10) and the compound of the formula (7).

A compound of the formula (1) in which p is 0 or 1, or q is 0, which issimilar to the compound of the formula (13) or the compound of theformula (15) can be synthesized in a manner similar to theabove-mentioned process.

The alkylenediamine derivative of the formula (1) can be converted intoa pharmacologically acceptable salt. Examples of the pharmacologicallyacceptable salt of the alkylenediamine derivative of the formula (1)include acid-addition salts such as salts with an inorganic acid (e.g.,hydrochloric acid, sulfuric acid, hydrobromic acid, or phosphoric acid),or an organic acid (e.g., fumaric acid, acetic acid, propionic acid,citric acid, tartaric acid, maleic acid, malic acid, oxalic acid,methanesulfonic acid, or p-toluenesulfonic acid).

Examples of the alkylenediamine derivatives represented by the formula(1) are described below:

(1) 2- 3-(4-phenoxypiperidino)propyl!-2H-1,2-benzothiazin-4(3H)-one1,1-dioxide

(2) 2- 3-(4-benzyloxypiperidino)propyl!-2H-1,2-benzothiazin-4(3H)-one1,1-dioxide

(3) 3- 3-(4-benzylpiperidino)propyl!-1H-2,3-benzothiazin-4(3H)-one2,2-dioxide

(4) 2-(3-morpholino-1-phenylpropyl)-2H-1,2-benzothiazin-3(4H)-one1,1-dioxide

(5) 3-(3-morpholino-1-phenylpropyl)-2H-1,3-benzothiazin-4(3H)-one1,1-dioxide

(6) 3-(2-hydroxy-3-morpholinopropyl)-1H-2,3-benzothiazin-4(3H)-one2,2-dioxide

(7) 3-(2-ethoxy-3-morpholinopropyl)-1H-2,3-benzothiazin-4(3H)-one2,2-dioxide

(8) 2-(2-hydroxy-3-morpholinopropyl)-2H-1,2-benzothiazin-4(3H)-one1,1-dioxide

(9) 3-(3-morpholino-3-phenylpropyl)-1H-2,3-benzothiazin-4(3H)-one2,2-dioxide

(10) 2- 3-(4-benzylpiperidino)propyl!-2H-1,2-benzothiazin-4(3H)-one1,1-dioxide

(11) 2- 3-(N-benzyl-N-butylamino)propyl!-2H-1,2-benzothiazin-4(3H)-one1,1-dioxide

(12) 2-3-(4-diphenylmethyl-1-piperazinyl)propyl!-2H-1,2-benzothiazin-4(3H)-one1,1-dioxide

(13) 2- 2-(4-benzylpiperidino)ethyl!-2H-1,2-benzothiazin-4(3H) -one1,1-dioxide

(14) 2- 3-(4-benzyl-1-piperazinyl)propyl!-2H-1,2-benzothiazin-4(3H)-one1,1-dioxide

(15) 2- 3-2-(1,2,3,4-tetrahydroisoquinolyl)!propyl!-2H-1,2-benzothiazin-4(3H)-one1,1-dioxide

(16) 2- 3-4-(4-methoxybenzyl)piperidino!propyl!-2H-1,2-benzothiazin-4(3H)-one1,1-dioxide

(17) 2-(3-morpholinopropyl)-2H-1,2-benzothiazin-4(3H)-one 1,1-dioxide

(18) 2-(3-diethylamino-1-phenylpropyl)-2H-1,2-benzothiazin-4(3H)-one1,1-dioxide

(19) 2-(1-phenyl-3-piperidinopropyl)-2H-1,2-benzothiazin-4(3H)-one1,1-dioxide

(20) 2-(3-morpholino-1-phenylpropyl)-2H-1,2-benzothiazin-4(3H) -one1,1-dioxide

(21) 2-(1-phenyl-3-thiomorpholinopropyl)-2H-1,2-benzothiazin-4(3H)-one1,1-dioxide

(22) 2-3-morpholino-1-(4-chlorophenyl)propyl!-2H-1,2-benzothiazin-4(3H)-one1,1-dioxide

(23) 3-(1-phenyl-3-piperidinopropyl)-1H-2,3-benzothiazin-4(3H)-one2,2-dioxide

(24) 3-(3-morpholino-1-phenylpropyl)-1H-2,3-benzotiazin-4(3H) -one2,2-dioxide

(25) 3-(3-diethylamino-1-phenylpropyl)-1H-2,3-benzothiazin-4(3H)-one2,2-dioxide

(26) 3-(1-phenyl-3-thiomorpholinopropyl)-1H-2,3-benzothiazin-4(3H)-one2,2-dioxide

(27) 3-3-morpholino-1-(4-chlorophenyl)propyl!-1H-2,3-benzothiazin-4(3H)-one2,2-dioxide

(28) 3-(3-morpholino-2-phenylpropyl)-1H-2,3-benzothiazin-4(3H) -one2,2-dioxide

(29) 2-(3-morpholino-3-phenylpropyl)-2H-1,2-benzothiazin-4(3H)-one1,1-dioxide

(30) 2-(3-chloropropyl)-2H-1,2-benzothiazin-4(3H)-one 1,1-dioxide

(31) 2- 3-(2,3-dihydro-1H-benzde!isoquinolin-2-yl)propyl!-2H-1,2-benzothiazin-4(3H)-one 1,1-dioxidehydrochloride

(32) 2-3-(4-cyano-4-phenylpiperidino)propyl!-2H-1,2-benzothiazin-4(3H)-one1,1-dioxide fumarate

(33) 2-(3-chloro-1-phenylpropyl)-2H-1,2-benzothiazin-4(3H) -one1,1-dioxide

(34) 2-3-(4-cyano-4-phenylpiperidino)-1-phenylpropyl!-2H-1,2-benzothiazin-4(3H)-one1,1-dioxide fumarate

Representative examples of the alkylenediamine derivatives of theinvention are set forth in Tables 1 and 2.

In Table 1, the compounds of the formula (2) and the compounds of theformula (3) are given, in which the symbols correspond to those seen inthe formulas (2) and (3). In Table 2, the compounds of the formula (13)and the compounds of the formula (15) are given, in which the symbolscorrespond to those seen in the formulas (13) and (15).

                                      TABLE 1                                     __________________________________________________________________________    (R.sup.1).sub.k                                                                     R.sup.2                                                                                 ##STR23##         k m n                                       __________________________________________________________________________    H     H        morpholino         1 1 1                                       H     H        4-benzylpiperidino 1 1 1                                       H     H        4-benzyloxypiperidino                                                                            1 1 1                                       H     H        benzylbutylamino   1 1 1                                       H     H        4-diphenylmethyl-1-piperazinyl                                                                   1 1 1                                       H     H        4-phenoxypiperidino                                                                              1 1 1                                       H     H        4-benzylpiperidino 1 1 0                                       H     H        4-benzyl-1-piperazinyl                                                                           1 1 1                                       H     H        1,2,3,4-tetrahydroisoquinolin-2-yl                                                               1 1 1                                       H     OH       morpholino         1 1 1                                       H     phenyl   diethylamino       1 0 2                                       H     phenyl   piperidino         1 0 2                                       H     phenyl   morpholino         1 0 2                                       H     phenyl   thiomorpholino     1 0 2                                       H     4-chlorophenyl                                                                         morpholino         1 0 2                                       H     phenyl   morpholino         1 2 0                                       H     H        4-(4-methoxybenzyl)piperidino                                                                    1 1 1                                       H     ethoxy   morpholino         1 1 1                                       H     phenyl   morpholino         1 1 1                                       5-chloro                                                                            H        4-benzylpiperidino 1 1 1                                       7-chloro                                                                            methyl   4-benzylpiperidino 1 0 2                                       5,7-dichloro                                                                        H        4-benzylpiperidino 2 0 2                                       5-fluoro                                                                            H        4-benzylpiperidino 1 0 2                                       5-methyl                                                                            H        4-benzylpiperidino 1 0 2                                       7-fluoro                                                                            H        4-benzylpiperidino 1 0 2                                       7-methyl                                                                            H        4-benzylpiperidino 1 0 2                                       5-methoxy                                                                           H        4-benzylpiperidino 1 0 2                                       7-methoxy                                                                           H        4-benzylpiperidino 1 0 2                                       5-chloro                                                                            H        4-benzyl-1-piperazinyl                                                                           1 0 2                                       7-chloro                                                                            H        4-benzyl-1-piperazinyl                                                                           1 0 2                                       5-fluoro                                                                            H        4-benzyl-1-piperazinyl                                                                           1 0 2                                       5-methyl                                                                            H        4-benzyl-1-piperazinyl                                                                           1 0 2                                       5-methoxy                                                                           H        4-benzyl-1-piperazinyl                                                                           1 0 2                                       7-fluoro                                                                            H        4-benzyl-1-piperazinyl                                                                           1 0 2                                       7-methyl                                                                            H        4-benzyl-1-piperazinyl                                                                           1 0 2                                       5-chloro                                                                            H        benzylbutylamino   1 0 2                                       5-fluoro                                                                            H        benzylbutylamino   1 0 2                                       5-methyl                                                                            H        benzylbutylamino   1 0 2                                       5-methoxy                                                                           H        benzylbutylamino   1 0 2                                       5-chloro                                                                            H        1,2,3,4-tetrahydroisoquinolin-2-yl                                                               1 0 2                                       5-fluoro                                                                            H        1,2,3,4-tetrahydroisoquinolin-2-yl                                                               1 0 2                                       7-chloro                                                                            H        1,2,3,4-tetrahydroisoquinolin-2-yl                                                               1 0 2                                       5-methyl                                                                            H        1,2,3,4-tetrahydroisoquinolin-2-yl                                                               1 0 2                                       5-chloro                                                                            H        4-benzyloxypiperidino                                                                            1 0 2                                       5-fluoro                                                                            H        4-benzyloxypiperidino                                                                            1 0 2                                       7-chloro                                                                            H        4-benzyloxypiperidino                                                                            1 0 2                                       5-methyl                                                                            H        4-benzyloxypiperidino                                                                            1 0 2                                       7-methyl                                                                            H        4-benzyloxypiperidino                                                                            1 0 2                                       5-chloro                                                                            H        4-phenoxypiperidino                                                                              1 0 2                                       5-fluoro                                                                            H        4-phenoxypiperidino                                                                              1 0 2                                       5-methyl                                                                            H        4-phenoxypiperidino                                                                              1 0 2                                       7-chloro                                                                            H        4-phenoxypiperidino                                                                              1 0 2                                       7-methyl                                                                            H        4-phenoxypiperidino                                                                              1 0 2                                       5-chloro                                                                            H        4-diphenylmethyl-1-piperazinyl                                                                   1 0 2                                       5-fluoro                                                                            H        4-diphenylmethyl-1-piperazinyl                                                                   1 0 2                                       5-methyl                                                                            H        4-diphenylmethyl-1-piperazinyl                                                                   1 0 2                                       7-chloro                                                                            H        4-diphenylmethyl-1-piperazinyl                                                                   1 0 2                                       7-methyl                                                                            H        4-diphenylmethyl-1-piperazinyl                                                                   1 0 2                                       5-chloro                                                                            H        4-(4-methoxybenzyl)piperidino                                                                    1 0 2                                       7-methyl                                                                            H        4-(4-methoxybenzyl)piperidino                                                                    1 0 2                                       5-chloro                                                                            H        4-(4-chlorobenzyl)piperidino                                                                     1 0 2                                       7-methyl                                                                            H        4-(4-chlorobenzyl)piperidino                                                                     1 0 2                                       5-chloro                                                                            H        4-(4-acetylbenzyl)piperidino                                                                     1 0 2                                       7-methyl                                                                            H        4-(4-acetylbenzyl)piperidino                                                                     1 0 2                                       5-chloro                                                                            H        4-(4-methylbenzyl)piperidino                                                                     1 0 2                                       7-methyl                                                                            H        4-(4-methylbenzyl)piperidino                                                                     1 0 2                                       5-chloro                                                                            H        4-(3-methoxybenzyl)piperidino                                                                    1 0 2                                       7-methyl                                                                            H        4-(2-chlorobenzyl)piperidino                                                                     1 0 2                                       5-chloro                                                                            H        3-benzylpiperidino 1 0 2                                       7-methyl                                                                            H        3-benzylpiperidino 1 0 2                                       5-chloro                                                                            H        4-(4-methoxybenzyl)-1-piperazinyl                                                                1 0 2                                       5-methyl                                                                            H        4-(4-methoxybenzyl)-1-piperazinyl                                                                1 0 2                                       7-methyl                                                                            H        4-(4-chlorobenzyl)-1-piperazinyl                                                                 1 0 2                                       5-chloro                                                                            H        6-methoxy-1,2,3,4-tetrahydroisoquinolin-2-yl                                                     1 0 2                                       7-methyl                                                                            H        6-methoxy-1,2,3,4-tetrahydroisoquinolin-2-yl                                                     1 0 2                                       5-chloro                                                                            H        6-chloro-1,2,3,4-tetrahydroisoquinolin-2-yl                                                      1 0 2                                       7-methyl                                                                            H        6-chloro-1,2,3,4-tetrahydroisoquinolin-2-yl                                                      1 0 2                                       5-chloro                                                                            H        4-(4-methoxybenzyl)oxypiperidino                                                                 1 0 2                                       5-chloro                                                                            H        4-(4-chlorobenzyl)oxypiperidino                                                                  1 0 2                                       5-chloro                                                                            H        4-(4-methoxybenzyl)phenoxypiperidino                                                             1 0 2                                       5-chloro                                                                            H        4-(4-chlorobenzyl)phenoxypiperidino                                                              1 0 2                                       H     H        4-(4-methoxybenzyl)piperidino                                                                    1 0 2                                       H     H        4-(4-chlorobenzyl)piperidino                                                                     1 0 2                                       H     H        4-(4-acetylbenzyl)piperidino                                                                     1 0 2                                       H     H        4-(4-methylbenzyl)piperidino                                                                     1 0 2                                       H     H        4-(3-methoxybenzyl)piperidino                                                                    1 0 2                                       H     H        4-(2-chlorobenzyl)piperidino                                                                     1 0 2                                       H     H        3-benzylpiperidino 1 0 2                                       H     H        4-(4-methoxybenzyl)-1-piperazinyl                                                                1 0 2                                       H     H        4-(4-chlorobenzyl)-1-piperazinyl                                                                 1 0 2                                       H     H        6-methoxy-1,2,3,4-tetrahydroisoquinolin-2-yl                                                     1 0 2                                       H     H        6-chloro-1,2,3,4-tetrahydroisoquinolin-2-yl                                                      1 0 2                                       H     H        4-diphenylmethyloxypiperidino                                                                    1 0 2                                       5-chloro                                                                            H        4-diphenylmethyloxypiperidino                                                                    1 0 2                                       7-methyl                                                                            H        4-diphenylmethyloxypiperidino                                                                    1 0 2                                       H     H        3-benzylthiopiperidino                                                                           1 0 2                                       H     H        3-phenylthiopiperidino                                                                           1 0 2                                       H     phenyl   morpholino         1 0 1                                       H     phenyl   morpholino         1 0 3                                       H     phenyl   4-acetyl-1-piperazinyl                                                                           1 0 2                                       H     4-chlorophenyl                                                                         morpholino         1 0 2                                       H     4-methylphenyl                                                                         morpholino         1 0 2                                       H     3-chlorophenyl                                                                         morpholino         1 0 2                                       H     2-chlorophenyl                                                                         morpholino         1 0 2                                       H     2,4-dichlorophenyl                                                                     thiomorpholino     1 0 2                                       H     4-chlorophenyl                                                                         thiomorpholino     1 0 2                                       H     4-methylphenyl                                                                         thiomorpholino     1 0 2                                       H     3-chlorophenyl                                                                         thiomorpholino     1 0 2                                       H     2-chlorophenyl                                                                         thiomorpholino     1 0 2                                       H     2,4-dichlorophenyl                                                                     thiomorpholino     1 0 2                                       H     4-fluorophenyl                                                                         thiomorpholino     1 0 2                                       H     4-fluorophenyl                                                                         morpholino         1 0 2                                       5-chloro                                                                            phenyl   morpholino         1 0 2                                       5-chloro                                                                            phenyl   thiomorpholino     1 0 2                                       5-fluoro                                                                            phenyl   morpholino         1 0 2                                       7-chloro                                                                            phenyl   morpholino         1 0 2                                       5-methyl                                                                            phenyl   morpholino         1 0 2                                       7-methyl                                                                            phenyl   morpholino         1 0 2                                       7-fluoro                                                                            phenyl   morpholino         1 0 2                                       5,7-dichloro                                                                        phenyl   morpholino         2 0 2                                       5-chloro                                                                            4-chlorophenyl                                                                         morpholino         1 0 2                                       5-chloro                                                                            3-chlorophenyl                                                                         morpholino         1 0 2                                       5-chloro                                                                            2-chlorophenyl                                                                         morpholino         1 0 2                                       5-chloro                                                                            phenyl   4-acetyl-1-piperazinyl                                                                           1 0 2                                       H     phenyl   4-benzyl-1-piperazinyl                                                                           1 0 2                                       H     OH       morpholino         1 0 2                                       H     ethoxy   morpholino         1 0 2                                       H     methyl   4-benzylpiperidino 1 0 2                                       H     phenyl   4-benzylpiperidino 1 0 2                                       H     2-thienyl                                                                              morpholino         1 0 2                                       H     2-furyl  morpholino         1 0 2                                       H     2-furyl  4-benzylpiperidino 1 0 2                                       H     H        4-(2-thienylmethyl)piperidino                                                                    1 0 2                                       H     H        4-(2-thienylmethyl)piperidino                                                                    1 0 3                                       H     allyl    morpholino         1 0 2                                       H     phenyl   benzylbutylamino   1 0 2                                       5-chloro                                                                            H        4-(2-thienylmethyl)piperidino                                                                    1 0 2                                       5-chloro                                                                            4-chlorophenyl                                                                         4-diphenylmethyl-1-piperazinyl                                                                   1 0 2                                       5-chloro                                                                            4-chlorophenyl                                                                         diethylamino       1 0 2                                       5-chloro                                                                            4-chlorophenyl                                                                         diethylamino       1 0 3                                       H     2-pyridyl                                                                              thiomorpholino     1 0 2                                       7-chloro                                                                            2-pyridyl                                                                              2-benzylpiperidino 1 0 2                                       H     H        2,3-dihydro-1H-benz de!-isoquinolin-2-yl                                                         1 1 1                                       H     H        4-phenylpiperidino 1 1 1                                       H     H        4-phenyl-1-piperazinyl                                                                           1 1 1                                       H     H        4-(2-thienylmethoxy)piperidino                                                                   1 1 1                                       H     H        4-(2-thienylmethyl)piperidino                                                                    1 1 1                                       H     H        4-(2-thienyl)-1-piperazinyl                                                                      1 1 1                                       __________________________________________________________________________

                  TABLE 2                                                         ______________________________________                                        (R.sup.1).sub.k                                                                       R.sup.2                                                                                   ##STR24##      k   m   n                                  ______________________________________                                        H       phenyl     morpholino      1   0   2                                  H       H          4-benzylpiperidino                                                                            1   0   2                                  H       H          4-diphenyl-1-   1   0   2                                                     piperazinyl                                                H       H          4-benzylpiperidino                                                                            1   0   1                                  H       H          4-benzylpiperidino                                                                            1   0   3                                  5-chloro                                                                              H          4-benzylpiperidino                                                                            1   0   2                                  H       phenyl     thiomorpholino  1   0   2                                  H       2-thienyl  morpholino      1   0   2                                  H       H          6-chloro-1,2,3,4-tetrahydro-                                                                  1   0   2                                                     isoquinolin-2-yl                                           7-chloro                                                                              H          6-chloro-1,2,3,4-tetrahydro-                                                                  1   0   2                                                     isoquinolin-2-yl                                           5,7-dichloro                                                                          phenyl     diethylamino    2   0   2                                  H       4-chlorophenyl                                                                           morpholino      1   0   2                                  5-chloro                                                                              ethoxy     4-benzylpiperidino                                                                            1   1   1                                  ______________________________________                                    

Next, in the formula (I), the halogen represented by R¹ preferably isfluorine, chlorine or bromine, and chlorine is most preferred. The alkylhaving 1-8 carbon atoms which is represented by R¹ preferably is methyl,ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, hexyl, heptyl, oroctyl. The haloalkyl having 1-4 carbon atoms preferably istrifluoromethyl, chloromethyl, or fluoromethyl. The alkoxy having 1-8carbon atoms preferably is methoxy, ethoxy, or propoxy. The aryloxyhaving 4-10 carbon atoms (which may have nucleus substituents such ashalogen, cyano, alkyl, alkoxy, amino, or alkoxycarbonyl) preferably isphenoxy or p-chlorophenoxy. The aralkyloxy having 5-14 carbon atoms (itsalkyl portion has 1-4 carbon atoms) preferably is benzyloxy,pyridylmethyloxy, naphthylmethyloxy, or thenyloxy. The alkylamino having1-8 carbon atoms preferably is methylamino, dimethylamino, ethylamino,propylamino, or isobutylamino. The aralkylamino having 5-14 carbon atoms(its alkyl portion has 1-4 carbon atoms, and which may have nucleussubstituents such as halogen, cyano, alkyl, alkoxy, amino, oralkoxycarbonyl) preferably is benzylamino or(4-chlorophenyl)methylamino. The arylamino having 4-10 carbon atoms(which may have nucleus substituents such as halogen, cyano, alkyl,alkoxy, amino, or alkoxycarbonyl) preferably is phenylamino orp-chlorophenylamino. The aliphatic acylamino having 1-8 carbon atompreferably is acetylamino or propionylamino. The alkoxycarbonyl having2-9 carbon atoms preferably is methoxycarbonyl, ethoxycarbonyl, orpropoxycarbonyl. The aralkyloxycarbonyl having 6-15 carbon atoms (itsalkyl portion has 1-4 carbon atoms) preferably is benzyloxycarbonyl,pyridylmethyloxycarbonyl, naphthylmethyloxycarbonyl, orthenyloxycarbonyl. The aryloxycarbonyl having 5-11 carbon atomspreferably is phenoxycarbonyl, naphthyloxycarbonyl, orthienyloxycarbonyl. The alkoxysulfonyl having 1-8 carbon atomspreferably is methoxysulfonyl or ethoxysulfonyl. The aralkyloxysulfonylhaving 5-14 carbon atoms (its alkyl portion has 1-4 carbon atoms)preferably is benzyloxysulfonyl, naphthylmethyloxysulfonyl, orthenyloxysulfonyl. The aryloxysulfonyl having 4-10 carbon atomspreferably is phenoxysulfonyl, naphthyloxysulfonyl, orthienyloxysulfonyl.

In the formula (I), particularly preferred for R¹ is hydrogen, halogen,or alkoxy having 1-8 carbon atoms.

In the formula (I), R² represents a phenyl, naphthyl, or aromaticheterocyclic group which may have one to five same or differentsubstituents. Preferred groups are phenyl, naphthyl, furan, thiophene,pyridine, quinoline, or indole, which may have one to five same ordifferent substituents.

Among the above-mentioned substituents, the halogen preferably isfluorine, chlorine, or bromine. The alkyl having 1-8 carbon atomspreferably is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl,hexyl, heptyl, or octyl. The haloalkyl having 1-4 carbon atomspreferably is trifluoromethyl, chloromethyl, or fluoromethyl. The alkoxyhaving 1-8 carbon atoms preferably is methoxy, ethoxy, or propoxy. Thearyloxy having 4-10 carbon atoms (which may have nucleus substituentssuch as halogen, cyano, alkyl, alkoxy, amino, or alkoxycarbonyl)preferably is phenoxy or p-chlorophenoxy. The aralkyloxy having 5-14carbon atoms (its alkyl portion has 1-4 carbon atoms) preferably isbenzyloxy, pyridylmethyloxy, naphthylmethyloxy, or thenyloxy. Thealkylamino having 1-8 carbon atoms preferably is methylamino,dimethylamino, ethylamino, propylamino, or isobutylamino. Thearalkylamino having 5-14 carbon atoms (its alkyl portion has 1-4 carbonatoms, and which may have nucleus substituents such as halogen, cyano,alkyl, alkoxy, amino, or alkoxycarbonyl) preferably is benzylamino or(4-chlorophenyl)methylamimo. The arylamino having 4-10 carbon atoms(which may have nucleus substituents such as halogen, cyano, alkyl,alkoxy, amino, or alkoxycarbonyl) preferably is phenylamino orp-chlorophenylamino. The aliphatic acylamino having 1-8 carbon atompreferably is acetylamino or propionylamino. The alkoxycarbonyl having2-9 carbon atoms preferably is methoxycarbonyl, ethoxycarbonyl, orpropoxycarbonyl. The aralkyloxycarbonyl having 6-15 carbon atoms (itsalkyl portion has 1-4 carbon atoms) preferably is benzyloxycarbonyl,pyridylmethyloxycarbonyl, naphthylmethyloxycarbonyl, orthenyloxycarbonyl. The aryloxycarbonyl having 5-11 carbon atomspreferably is phenoxycarbonyl, pyridyloxycarbonyl, naphthyloxycarbonyl,or thienyloxycarbonyl. The alkoxysulfonyl having 1-8 carbon atomspreferably is methoxysulfonyl or ethoxysulfonyl. The aralkyloxysulfonylhaving 5-14 carbon atoms (its alkyl portion has 1-4 carbon atoms)preferably is benzyloxysulfonyl, naphthylmethyloxysulfonyl, orthenyloxysulfonyl. The aryloxysulfonyl having 4-10 carbon atomspreferably is phenoxysulfonyl, naphthyloxysulfonyl, orthienyloxysulfonyl.

Preferred for R² is phenyl or thienyl which may have one to five same ordifferent substituents. More preferred is phenyl having no substituents,or phenyl having, as substituent, one to five of alkyl having 1-8 carbonatoms, alkoxy having 1-8 carbon atoms, halogen, or haloalkyl having 1-8carbon atoms. Particularly preferred is phenyl having no substituents orphenyl having one substituent such as halogen or alkoxy having 1-8carbon atoms.

In the formula (I), the alkyl having 1-8 carbon atoms which isrepresented by R³ or R⁴ preferably is methyl, ethyl, propyl, isopropyl,butyl, or isobutyl. The aralkyl having 5-14 carbon atoms (its alkylportion has 1-4 carbon atoms) preferably is benzyl, phenylethyl, orphenylpropyl. The aryl having 4-10 carbon atoms preferably is phenyl,pyridyl, or naphthyl.

The five to seven membered heterocyclic group represented by the formula(II) formed by the combination of R³, R⁴ and the nitrogen atom to whichR³ and R⁴ are attached preferably is morpholino, piperidino,homomorpholino, 1-pyrrolidinyl, thiomorpholino, 1-piperazinyl,1-perhydroazepinyl, S-oxythiomorpholino, or S,S-dioxy-thiomorpholino.

The alkyl having 1-8 carbon atoms which is represented by R⁵ of theformula (III) for Z of the formula (II) preferably is methyl, ethyl,propyl, isopropyl, butyl, or isobutyl. The aralkyl having 5-14 carbonatoms (its alkyl has 1-4 carbon atoms) preferably is benzyl,phenylethyl, or phenylpropyl. The alkoxycarbonyl having 2-9 carbon atomspreferably is methoxycarbonyl, ethoxycarbonyl, or propoxycarbonyl. Thearalkyloxycarbonyl having 6-15 carbon atoms (its alkyl portion has 1-4carbon atoms) preferably is benzyloxycarbonyl, pyridylmethyloxycarbonyl,naphthylmethyloxycarbonyl, or thenyloxycarbonyl. The aryloxycarbonylhaving 5-11 carbon atoms preferably is phenoxycarbonyl,naphthyloxycarbonyl, or thienyloxycarbonyl.

Among the substituents which may be attached to the five to sevenmembered heterocyclic group of the formula (II), the alkyl having 1-5carbon atoms preferably is methyl, ethyl, propyl, isopropyl, butyl, orisobutyl. The aralkyl having 5-14 (its alkyl portion has 1-4 carbonatom) preferably is benzyl, phenylethyl, or phenylpropyl. The alkoxyhaving 1-5 carbon atoms preferably is methoxy, ethoxy, or propoxy. Thealkoxycarbonyl having 2-6 carbon atoms preferably is methoxycarbonyl,ethoxycarbonyl, or propoxycarbonyl. The aralkyloxycarbonyl having 6-15carbon atoms (its alkyl portion has 1-4 carbon atoms) preferably isbenzyloxycarbonyl, pyridylmethyloxycarbonyl, naphthylmethyloxycarbonyl,or thenyloxycarbonyl. The aryloxycarbonyl having 5-11 carbon atomspreferably is phenoxycarbonyl, naphthyloxycarbonyl, orthienyloxycarbonyl. The aliphatic acyl having 1-8 carbon atomspreferably is formyl, acetyl, or propionyl. The aromatic acyl having5-11 carbon atoms preferably is benzoyl or phthaloyl. If the two or moresubstituents are attached, these substituents may be the same ordifferent.

The five to seven membered heterocyclic group represented by the formula(II) preferably is morpholino, piperidino, homomorpholino,1-pyrrolidinyl, thiomorpholino, 1-piperazinyl, 1-perhydroazepinyl,S-oxythiomorpholino, or S,S-dioxythiomorpholino which may not havesubstituents or may have substituents such as alkyl having 1-8 carbonatoms, phenyl, acyl having 1-8 carbon atoms, carbamoyl, or 2-pyrimidinylon its carbon and/or nitrogen atom.

In the formula (I), m preferably is 1 or 2, and 1 is most preferred. npreferably is 0, 1, or 2, and 0 is most preferred. p preferably is 0,and q preferably is 1, 2 or 3. The alkylenediamine derivative of theformula (I) in which x is 2 and y is 1 corresponds to thealkylenediamine derivative of the formula (IV). The alkylenediaminederivative of the formula (I) in which x is 1 and y is 1 corresponds tothe alkylenediamine derivative of the formula (V). The alkylenediaminederivative of the formula (I) in which x is 2 and y is 0 corresponds tothe alkylenediamine derivative of the formula (VI).

The alkylenediamine derivative of the formula (I) can be prepared byreacting a compound having the formula (VII): ##STR25## in which R¹, m,x and y have the same meanings as defined in the formula (I)

with a compound having the formula (VIII): ##STR26## in which R², R³,R⁴, n, p and q have the same meanings as defined in the formula (I), andQ is a releasable group such as halogen, tosyloxy, or mesyloxy.

In the above-mentioned preparation process, the compound of the formula(VII) and the compound of the formula (VIII) are caused to react at atemperature from room temperature to the reflux temperature for 1 to 50hours, in an organic solvent such as acetone, dimethylformamide, methylethyl ketone, or isobutyl methyl ketone, in the presence of a carbonatesuch as potassium carbonate, sodium carbonate, or cesium carbonate, toprepare the compound of the formula (I). In the reaction, 1 to 2 molesof the compound of the formula (VIII) and the 2 to 8 moles of thecarbonate are preferably employed per one mole of the compound of theformula (VII). The compound of the formula (VIII) is preferably employedin its stable hydrochloride form.

Alternatively, the alkylenediamine derivative of the formula (I) can beprepared by reacting a compound of the formula (IX): ##STR27## in whichR¹, R², m, n, p, q, x and y have the same meanings as defined in theformula (I), and Q is a releasable group such as halogen, tosyloxy, ormesyloxy, with a compound having the formula (X): ##STR28## in which R³and R⁴ have the same meanings as defined in the formula (I).

In the above-mentioned preparation process, the compound of the formula(IX) and the compound of the formula (X) are caused to react at 50° to150° C. for 1 to 20 hours, generally, in the absence of a solvent. Ifnecessary, a solvent which does not participate in the reaction can beemployed.

The alkylenediamine derivative of the formula (I) can be converted intoa pharmacologically acceptable salt. Examples of the pharmacologicallyacceptable salt of the alkylenediamine derivative of the formula (I)include acid-addition salts such as salts with an inorganic acid (e.g.,hydrochloric acid, sulfuric acid, hydrobromic acid, or phosphoric acid),or an organic acid (e.g., fumaric acid, acetic acid, propionic acid,citric acid, tartaric acid, maleic acid, malic acid, oxalic acid,methanesulfonic acid, or p-toluenesulfonic acid).

Examples of the alkylenediamine derivatives represented by the formula(I) are described below:

(1) 2- 1-phenyl-3-(1-pyrrolidinyl)!propyl-1,2-benzisothiazol-3(2H)-one1,1-dioxide

(2) 2-(1-phenyl-3-thiomorpholino)propyl-1,2-benzisothiazol-3(2H)-one1,1-dioxide

(3) 2-(2-morpholino-1-phenyl)ethyl-1,2-benzisothiazol-3(2H)-one1,1-dioxide

(4) 2-(4-morpholino-1-phenyl)butyl-1,2-benzisothiazol-3(2H)-one1,1-dioxide

(5) 2-(1-phenyl-3-piperidino)propyl-1,2-benzisothiazol-3(2H)-one1,1-dioxide

(6) 2-3-(perhydroazepin-1-yl)-1-phenyl!propyl-1,2-benzisothiazol-3(2H)-one1,1-dioxide

(7) 2-3-(4-methylpiperidino)-1-phenyl!propyl-1,2-benzisothiazol-3(2H)-one1,1-dioxide

(8) 2-3-(4-carbamoylpiperidino)-1-phenyl!propyl-1,2-benzisothiazol-3(2H)-one1,1-dioxide

(9) 2-(3-morpholino-1-phenyl)propyl-1,2-benzisothiazol-3(2H)-one1,1-dioxide

(10) 2-3-(4-ethyl-1-piperazinyl)-1-phenyl!propyl-1,2-benzisothiazol-3(2H)-one1,1-dioxide

(11) 2-3-(4-acetyl-1-piperazinyl)-1-phenyl!propyl-1,2-benzisothiazol-3(2H)-one1,1-dioxide

(12) 2-1-phenyl-3-(4-(2-pyrimidinyl)-1-piperazinyl!propyl-1,2-benzisothiazol-3(2H)-one1,1-dioxide

(13) 2-1-(4-chlorophenyl)-3-piperidino!propyl-1,2-benzisothiazol-3(2H)-one1,1-dioxide

(14) 2-1-(4-chlorophenyl)-3-morpholino!propyl-1,2-benzisothiazol-3(2H)-one1,1-dioxide

(15) 2-1-(4-methoxyphenyl)-3-piperidino!propyl-1,2-benzisothiazol-3(2H)-one1,1-dioxide

(16)6-chloro-2-(1-phenyl-3-piperidino)propyl-1,2-benzisothiazol-3(2H)-one1,1-dioxide

(17)6-chloro-2-(3-morpholino-1-phenyl)propyl-1,2-benzisothiazol-3(2H)-one1,1-dioxide

(18)6-methoxy-2-(1-phenyl-3-piperidino)propyl-1,2-benzisothiazol-3(2H)-one1,1-dioxide

(19)6-methoxy-2-(3-morpholino-1-phenyl)propyl-1,2-benzisothiazol-3(2H)-one1,1-dioxide

(20)4-chloro-2-(3-piperidino-1-phenyl)propyl-1,2-benzisothiazol-3(2H)-one1,1-dioxide

(21) 2-(1-phenyl-3-thiomorpholino)propyl-1,2-benzisothiazol-3(2H)-one1,1,S-trioxide

(22) 2-(1-phenyl-3-thiomorpholino)propyl-1,2-benzisothiazol-3(2H)-one1,1,S,S-tetraoxide

(23) 2-3-(2-nethylthiomorpholino)-1-phenyl!propyl-1,2-benzisothiazol-3(2H)-one1,1-dixoide

(24) 2-3-(3-methylthiomorpholino)-1-phenyl!propyl-1,2-benzisothiazol-3(2H)-one1,1-dixoide

(25) 2-3-(2,2-dimethylthiomorpholino)-1-phenyl!propyl-1,2-benzisothiazol-3(2H)-one1,1-dioxide

(26) 2-3-(2,6-dimethylthiomorpholino)-1-phenyl!propyl-1,2-benzisothiazol-3(2H)-one1,1-dioxide

(27) 2-1-phenyl-3-(2-phenylthiomorpholino)!propyl-1,2-benzisothiazol-3(2H)-one1,1-dioxide

(28) 2-1-(4-fluorophenyl)-3-thiomorpholino!propyl-1,2-benzisothiazol-3(2H)-one1,1-dioxide

(29) 2-(3-dimethylamino-1-phenyl)propyl-1,2-benzisothiazol-3(2H)-one1,1-dioxide

(30) 2-(3-diethylamino-1-phenyl)propyl-1,2-benzisothiazol-3(2H)-one1,1-dioxide

(31) 2-(3-benzylethylamino-1-phenyl)propyl-1,2-benzisothiazol-3(2H)-one1,1-dioxide

(32) 2-(3-morpholino-1-phenyl)propyl-1,2-benzisothiazol-3(2H)-one1-oxide

(33) 2-(3-piperidino-1-phenyl)propyl-1,2-benzisothiazoline 1,1-dioxide

(34) 2-(3-morpholino-1-phenyl)propyl-1,2-benzisothiazoline 1,1-dioxide

Representative examples of the alkylenediamine derivatives of theformula (I) according to the invention are set forth in Tables 3, inwhich the symbols correspond to those seen in the formula (I).

                                      TABLE 3                                     __________________________________________________________________________    No.                                                                              (R.sup.1).sub.m                                                                     R.sup.2                                                                              --NR.sup.3 R.sup.4                                                                     m n p q  x y                                         __________________________________________________________________________     1 H     phenyl 1-pyrrolidinyl                                                                         1 0 0 2  2 1                                          2 H     phenyl thiomorpholino                                                                         1 0 0 2  2 1                                          3 H     phenyl morpholino                                                                             1 0 0 1  2 1                                          4 H     phenyl morpholino                                                                             1 0 0 3  2 1                                          5 H     phenyl piperidino                                                                             1 0 0 2  2 1                                          6 H     phenyl 1-perhydroazepinyl                                                                     1 0 0 2  2 1                                          7 H     phenyl 4-methylpiperidino                                                                     1 0 0 2  2 1                                          8 H     phenyl 4-carbamoyl-                                                                           1 0 0 2  2 1                                                         piperidino                                                     9 H     phenyl morpholino                                                                             1 0 0 2  2 1                                         10 H     phenyl 4-ethyl-1-                                                                             1 0 0 2  2 1                                                         piperazinyl                                                   11 H     phenyl 4-acetyl-1-                                                                            1 0 0 2  2 1                                                         piperazinyl                                                   12 H     phenyl 4-(2-pyrimidinyl)-                                                                     1 0 0 2  2 1                                                         1-piperazinyl                                                 13 H     4-chloro-                                                                            piperidino                                                                             1 0 0 2  2 1                                                  phenyl                                                               14 H     4-chloro-                                                                            morpholino                                                                             1 0 0 2  2 1                                                  phenyl                                                               15 H     4-methoxy-                                                                           piperidino                                                                             1 0 0 2  2 1                                                  phenyl                                                               16 6-chloro                                                                            phenyl piperidino                                                                             1 0 0 2  2 1                                         17 6-chloro                                                                            phenyl morpholino                                                                             1 0 0 2  2 1                                         18 6-methoxy                                                                           phenyl piperidino                                                                             1 0 0 2  2 1                                         19 6-methoxy                                                                           phenyl morpholino                                                                             1 0 0 2  2 1                                         20 4-chloro                                                                            phenyl piperidino                                                                             1 0 0 2  2 1                                         21 H     phenyl thiomorpholino-                                                                        1 0 0 2  2 1                                                         oxide                                                         22 H     phenyl thiomorpholino-                                                                        1 0 0 2  2 1                                                         dioxide                                                       23 H     phenyl 2-methylthio-                                                                          1 0 0 2  2 1                                                         morpholino                                                    24 H     phenyl 3-methylthio-                                                                          1 0 0 2  2 1                                                         morpholino                                                    25 H     phenyl 2,2-dimethyl-                                                                          1 0 0 2  2 1                                                         thiomorpholino                                                26 H     phenyl 2,6-dimethyl-                                                                          1 0 0 2  2 1                                                         thiomorpholino                                                27 H     phenyl 2-phenylthio-                                                                          1 0 0 2  2 1                                                         morpholino                                                    28 H     4-fluoro-                                                                            thiomorpholino                                                                         1 0 0 2  2 1                                                  phenyl                                                               29 H     phenyl dimethylamino                                                                          1 0 0 2  2 1                                         30 H     phenyl diethylamino                                                                           1 0 0 2  2 1                                         31 H     phenyl benzylethylamino                                                                       1 0 0 2  2 1                                         32 H     phenyl morpholino                                                                             1 0 0 2  1 1                                         33 H     phenyl piperidino                                                                             1 0 0 2  2 0                                         34 H     phenyl morpholino                                                                             1 0 0 2  2 0                                         35 4-bromo                                                                             phenyl morpholino                                                                             1 0 0 2  2 1                                         36 6-bromo                                                                             phenyl morpholino                                                                             1 0 0 2  2 1                                         37 4-fluoro                                                                            phenyl morpholino                                                                             1 0 0 2  2 1                                         38 6-fluoro                                                                            phenyl morpholino                                                                             1 0 0 2  2 1                                         39 4-methoxy                                                                           phenyl morpholino                                                                             1 0 0 2  2 1                                         40 4-cyano                                                                             phenyl morpholino                                                                             1 0 0 2  2 1                                         41 4-methyl                                                                            phenyl morpholino                                                                             1 0 0 2  2 1                                         42 6-cyano                                                                             phenyl morpholino                                                                             1 0 0 2  2 1                                         43 6-methyl                                                                            phenyl morpholino                                                                             1 0 0 2  2 1                                         44 4-hydroxy                                                                           phenyl morpholino                                                                             1 0 0 2  2 1                                         45 6-phenoxy                                                                           phenyl morpholino                                                                             1 0 0 2  2 1                                         46 4-acetyl-                                                                           phenyl morpholino                                                                             1 0 0 2  2 1                                            amino                                                                      47 H     2-thienyl                                                                            morpholino                                                                             1 0 0 2  2 1                                         48 4-chloro                                                                            2-thienyl                                                                            morpholino                                                                             1 0 0 2  2 1                                         49 4-bromo                                                                             2-thienyl                                                                            morpholino                                                                             1 0 0 2  2 1                                         50 4-fluoro                                                                            2-thienyl                                                                            morpholino                                                                             1 0 0 2  2 1                                         51 4-methoxy                                                                           2-thienyl                                                                            morpholino                                                                             1 0 0 2  2 1                                         52 H     2-furyl                                                                              morpholino                                                                             1 0 0 2  2 1                                         53 4-chloro                                                                            2-furyl                                                                              morpholino                                                                             1 0 0 2  2 1                                         54 4-bromo                                                                             2-furyl                                                                              morpholino                                                                             1 0 0 2  2 1                                         55 4-fluoro                                                                            2-furyl                                                                              morpholino                                                                             1 0 0 2  2 1                                         56 4-methoxy                                                                           2-furyl                                                                              morpholino                                                                             1 0 0 2  2 1                                         57 4-chloro                                                                            phenyl thiomorpholino                                                                         1 0 0 2  2 1                                         58 4-bromo                                                                             phenyl thiomorpholino                                                                         1 0 0 2  2 1                                         59 4-fluoro                                                                            phenyl thiomorpholino                                                                         1 0 0 2  2 1                                         60 4-methoxy                                                                           phenyl thiomorpholino                                                                         1 0 0 2  2 1                                         61 H     2-thienyl                                                                            thiomorpholino                                                                         1 0 0 2  2 1                                         62 H     2-furyl                                                                              thiomorpholino                                                                         1 0 0 2  2 1                                         63 H     phenyl morpholino                                                                             1 0 1 1  2 1                                         64 H     phenyl morpholino                                                                             1 0 2 0  2 1                                         65 H     phenyl thiomorpholino                                                                         1 0 1 1  2 1                                         66 H     phenyl thiomorpholino                                                                         1 0 2 0  2 1                                         67 H     phenyl homomorpholino                                                                         1 0 0 2  2 1                                         68 4-chloro                                                                            phenyl homomorpholino                                                                         1 0 0 2  2 1                                         69 4-bromo                                                                             phenyl homomorpholino                                                                         1 0 0 2  2 1                                         70 4-fluoro                                                                            phenyl homomorpholino                                                                         1 0 0 2  2 1                                         71 4-methoxy                                                                           phenyl homomorpholino                                                                         1 0 0 2  2 1                                         72 5,6-  phenyl morpholino                                                                             2 0 0 2  2 1                                            dichloro                                                                   73 5,6-  phenyl thiomorpholino                                                                         2 0 0 2  2 1                                            dichloro                                                                   74 5,6-  phenyl piperidino                                                                             2 0 0 2  2 1                                            dichloro                                                                   75 5,6-  phenyl homomorpholino                                                                         2 0 0 2  2 1                                            dichloro                                                                   76 5,6-  phenyl morpholino                                                                             2 0 0 2  2 1                                            dimethoxy                                                                  77 5,6-  phenyl thiomorpholino                                                                         2 0 0 2  2 1                                            dimethoxy                                                                  78 5,6-  phenyl piperidino                                                                             2 0 0 2  2 1                                            dimethoxy                                                                  79 5,6-  phenyl homomorpholino                                                                         2 0 0 2  2 1                                            dimethoxy                                                                  80 4-chloro                                                                            4-chloro-                                                                            morpholino                                                                             1 0 0 2  2 1                                                  phenyl                                                               81 4-chloro                                                                            4-chloro-                                                                            thiomorpholino                                                                         1 0 0 2  2 1                                                  phenyl                                                               82 4-chloro                                                                            4-chloro-                                                                            piperidino                                                                             1 0 0 2  2 1                                                  phenyl                                                               83 4-bromo                                                                             4-chloro-                                                                            morpholino                                                                             1 0 0 2  2 1                                                  phenyl                                                               84 4-bromo                                                                             4-chloro-                                                                            thiomorpholino                                                                         1 0 0 2  2 1                                                  phenyl                                                               85 4-bromo                                                                             4-fluoro-                                                                            morpholino                                                                             1 0 0 2  2 1                                                  phenyl                                                               86 4-fluoro                                                                            4-chloro-                                                                            morpholino                                                                             1 0 0 2  2 1                                                  phenyl                                                               87 4-fluoro                                                                            4-chloro-                                                                            thiomorpholino                                                                         1 0 0 2  2 1                                                  phenyl                                                               88 H     2,6-dichloro-                                                                        morpholino                                                                             1 0 0 2  2 1                                                  phenyl                                                               89 H     3,5-dichloro-                                                                        morpholino                                                                             1 0 0 2  2 1                                                  phenyl                                                               90 H     2,6-dichloro-                                                                        thiomorpholino                                                                         1 0 0 2  2 1                                                  phenyl                                                               91 H     3,5-dichloro-                                                                        thiomorpholino                                                                         1 0 0 2  2 1                                                  phenyl                                                               92 4-methyl                                                                            4-chloro                                                                             morpholino                                                                             1 0 0 2  2 1                                         93 4-chloro                                                                            4-methyl                                                                             morpholino                                                                             1 0 0 2  2 1                                         94 5,6-  2,6-dichloro-                                                                        morpholino                                                                             2 0 0 2  2 1                                            dichloro                                                                            phenyl                                                               95 4-chloro                                                                            4-chlorophenyl                                                                       morpholino                                                                             1 0 1 1  2 1                                         96 4-chloro                                                                            4-chlorophenyl                                                                       morpholino                                                                             1 0 2 0  2 1                                         97 6-isopropyl                                                                         phenyl morpholino                                                                             1 0 0 2  2 1                                         98 6-n-butyl                                                                           phenyl morpholino                                                                             1 0 0 2  2 1                                         99 H     4-isopropyl-                                                                         morpholino                                                                             1 0 0 2  2 1                                                  phenyl                                                               100                                                                              H     4-isoamyl-                                                                           morpholino                                                                             1 0 0 2  2 1                                                  phenyl                                                               101                                                                              H     β-naphthyl                                                                      morpholino                                                                             1 0 0 2  2 1                                         102                                                                              H     4-pyridyl                                                                            morpholino                                                                             1 0 0 2  2 1                                         __________________________________________________________________________

The compound of the invention was evaluated in urinating contraction ofbladder by the following test method.

TEST METHOD

A male rat (Wistar strain) was fixed on his back under urethaneanesthesia (1.5 g/kg, S.C.). A tracheal cannula was inserted into therat to respire easily, and its hypogastrium was subjected to mediandissection for exposing its bladder. A small opening was made on the topof the bladder to remove urine. To the bladder was inserted apolyethylene cannula. The bladder system was made to closed system byligating urethra and ureter.

A physiological saline was injected into the bladder of rat at a rate of0.05 mL/min. using a continuous injector so as to cause periodicalurinating contraction. The intravesical pressure of the bladder wasmeasured by means of a pressure transducer. The measured value wasrecorded on a pen-writing recorder. The compound to be tested wasdissolved in a physiological saline and administered into the femoralvein using the polyethylene cannula.

METHOD OF EVALUATION

The action for relieving urinating contraction was evaluated bymeasuring a period of time during which the rhythimic bladdercontraction was inhibited (period of contraction inhibition).

The compounds tested were those obtained in the working examples. Theperiod of contraction inhibition measured on each compound is set forthin Table 4.

                  TABLE 4                                                         ______________________________________                                                                            Period of Con-                                     Mouse LD.sub.50                                                                         Dose      Number of                                                                            traction Inhi-                            Compound (mg/kg/ i.v.)                                                                           (mg/kg i.v.)                                                                            Samples                                                                              bition(min.)                              ______________________________________                                        Control  --        --        6      1.6                                       (Physi. Saline)                                                               Example 20 A!                                                                          >120      12        6      9.7                                       Example 20 B!                                                                          140       6         2      0.4                                       Example 20 C!                                                                          180       6         2      6.0                                       Example 24 A!                                                                          62        12        8      5.6                                       Example 24 B!                                                                          32        6         2      8.5                                       Example 24 C!                                                                          167       6         2      0.7                                       Example 21                                                                             >100      10        1      7.0                                       Example 26                                                                             37        4         2      7.3                                       Example 10                                                                             3         8         2      14.5                                      Example 11                                                                             37        8         4      3.9                                       Example 12                                                                             --        8         2      2.5                                       Example 1                                                                              --        1         3      2.8                                       Example 14                                                                             17        8         3      12.7                                      Example 15                                                                             23        8         3      4.7                                       Example 3                                                                              --        8         2      2                                         Example 2                                                                              --        8         2      16                                        Example 13                                                                             --        8         2      18                                        Example 16                                                                             --        8         3      --                                        Example 31                                                                             --        8         3      --                                        Example 32                                                                             --        8         3      6                                         Example 34                                                                             --        8         2      3                                         Example IX                                                                             48        5         4      10.7                                      Example XI                                                                             170       17        2      6.0                                       Example II                                                                             47        5         10     3.8                                       Example XII                                                                            >200      20        2      3.5                                       ______________________________________                                    

The results seen in Table 4 clearly indicate that the compound of theinvention is effective in relieving urinating contraction. Further, thetoxicity of the compound is set forth in Table 4 in terms of LD₅₀(mg/kg) calculated by Probit method.

The alkylenediamine derivative or its pharmacologically acceptable saltaccording to the invention is useful as an active ingredient for apharmaceutical for treatment of dysuria.

The pharmaceutical for treatment of dysuria according to the inventioncan be used either in a general preparation form for oral administrationor in the form for parenteral adminstration such as injections andsuppositories. Preparation forms for oral administration may be tablets,capsules, powder, granules, syrup and the like. Preparation forms forparenteral administration may be injections and suppositories and thelike. For the formulation of these preparations, excipients,disintegrants, binders, lubricants, pigments, diluents and the likewhich are commonly employed in the art may be used. The excipients mayinclude glucose, lactose and the like. Starch, carboxymethylcellulosecalcium and the like may be used as the disintegrants. Magnesiumstearate, talc and the like may be used as the lubricants. The bindersmay be hydroxypropylcellulose, gelatin, polyvinylpyrrolidone and thelike.

The dose may usually be about 0.1 mg/day to 10.0 mg/day in the case ofan injectable preparation and about 1.0 mg/day to 500 mg/day in the caseof oral administration, both for adult. The dose may be either increasedor decreased depending upon the age and conditions of patients.

The present invention is further described by the following examples.

EXAMPLE 1 2-3-(4-Phenoxypiperidino)propyl!-2H-1,2-benzothiazin-4(3H)-one 1,1-dioxideHydrochloride (1) 2-(3-Chloropropyl)-2H-1,2-benzothiazin-4(3H)-one1,1-dioxide Ethylene Ketal

In 1,2-dimethoxyethane (450 mL) was suspended 60% sodium hydride (2.0 g,502 mmol.), and then 2H-1,2-benzothiazin-4(3H)-one 1,1-dioxide ethyleneketal (12.06 g, 50 mmol.) was added to the suspension. The suspensionwas heated to 100° C. for 1 hour under stirring. The reaction liquid wascooled to 50° C., and to this was added a solution of1-bromo-3-chloropropane (23.62 g, 150 mmol.) in 1,2-dimethoxyethane (50mL). The mixture was heated to 100° C. for 21 hours under refluxing. Thereaction liquid was filtered to remove insolubles and the solvent wasevaporated to give a residue. The residue was treated with water andether, and the organic layer was taken out. The organic solution waswashed with water and a saturated aqueous sodium chloride solution, anddried over anhydrous sodium sulfate. The solvent was evaporated to leavethe desired compound (8.89 g, yield 56%) as a yellow oil.

¹ H-NMR (CDCl₃) δ: 2.0-2.1 (2H, m), 3.62 (2H, t, J=6 Hz), 3.71 (2H, t,J=6 Hz), 3.91 (2H, s), 4.1-4.2 (2H, m), 4.2-4.3 (2H, m), 7.4-7.6 (3H,m), 7.7-7.8 (1H, m).

(2) 2- 3-(4-Phenoxypiperidino)propyl!-2H-1,2-benzothiazin-4(3H)-one1,1-Dioxide Ethylene Ketal

In dichloromethane (1 mL) were dissolved2-(3-chloropropyl)-2H-1,2-benzothiazin-4(3H)-one 1,1-dioxide ethyleneketal (830 mg, 2.6 mmol.) obtained in (1) and 4-phenoxypiperidine (500mg, 2.6 mmol.). From the solution was distilled off dichloromethane, andthe residue was heated to 110° C. for 5.5 hours under stirring and innitrogen atmosphere. To the reaction liquid were added an aqueoussaturated sodium hydrogen carbonate solution and ethyl acetate, and theorganic layer was taken out. The organic solution was washed with waterand an aqueous saturated sodium chloride solution, and then dried overanhydrous sodium sulfate. The solvent was distilled off to leave aresidue. The residue was treated by silica gel column chromatography(chloroform/methanol=40/1) to obtain the desired compound (700 mg, yield58%) as a yellow oil.

¹ H-NMR (CDCl₃) δ: 1.7-1.9 (4H, m), 1.9-2.1 (2H, m), 2.2-2.3 (2H, m),2.4-2.5 (2H, m), 2.7-2.8 (2H, m), 3.5-3.6 (2H, m), 3.91 (2H, s), 4.1-4.2(2H, m), 4.3-4.4 (3H, m), 6.9-7.0 (3H, m), 7.2-7.3 (2H, m), 7.5-7.6 (3H,m), 7.75-7.8 (1H, m).

(3) 2- 3-(4-Phenoxypiperidino)propyl!-2H-1,2-benzothiazin-4(3H)-one1,1-Dioxide Hydrochloride

In methanol (10 mL) was dissolved 2-3-(4-phenoxypiperidino)propyl!-2H-1,2-benzothiazon-4(3H)-one 1,2-dioxideethylene ketal (700 mg, 1.5 mmol.) obtained in (2). To the obtainedsolution was added 3N hydrochloric acid (10 mL), and the mixture washeated under refluxing for 15 min. The solvent was distilled off fromthe reaction liquid. To the residue was added water, and the mixture waskept in a cooled place. Crude crystals deposited were collected byfiltration, and recrystallized from dichloromethane/methyl ethyl ketoneto give the desired compound (440 mg, yield 64%) as a white crystallineproduct.

M.P.: 204°-207° C., IR (KBr) cm⁻¹ : 3400, 2500, 1700, 1600, 1590, 1490,1340, 1240, 1230, 1170, 1120, 1110, 1050, 975, 780, 750, 690, 570. ¹H-NMR (CDCl₃) δ: 2.1-2.3 (4H, m), 2.5-2.7 (2H, m), 3.0-3.2 (4H, m),3.3-3.4 (2H, m), 3.4-3.5 (2H, m), 4.50 (2H, s), 4.6-4.7 (1H, m), 6.9-7.0(3H, m), 7.2-7.3 (2H, m), 7.7-7.9 (3H, m), 8.0-8.1 (1H, m).

EXAMPLE 2 2-3-(4-Benzyloxypiperidino)propyl!-2H-1,2-benzothiazin-4(3H)-one1,1-Dioxide Hydrochloride (1) 2-3-(4-Benzyloxypiperidino)propyl!-2H-1,2-benzothiazin-4(3H)-one1,1-Dioxide Free Base

In 1,2-dimethoxyethane (40 mL) was suspended 60% sodium hydride (180 mg,4.5 mmol.), and then 2H-1,2-benzothiazin-4(3H)-one 1,1-dioxide ethyleneketal (1.00 g, 4.1 mmol.) was added to the suspension. The suspensionwas heated for 1 hour under stirring. The reaction liquid was cooled to50° C., and to this was added a solution of4-benzyloxy-1-(3-chloropropyl)piperidine (1.11 g, 4.1 mmol.) in1,2-dimethoxyethane (10 mL). The mixture was further heated for 20 hoursunder refluxing. The reaction liquid was filtered to remove insolublesand the solvent was distilled off to give a residue. To the residue wereadded aqueous 9% hydrochloric acid (30 mL) and methanol (30 mL), and themixture was heated for 15 min. under refluxing. The reaction liquid wasplaced under reduced pressure to distill methanol off. The residue wastreated with ice-water, and the deposited oil was extracted withdichloromethane. The dichloromethane portion was washed with water andan aqueous saturated sodium chloride solution, and dried over anhydroussodium sulfate. The solvent was distilled off to leave a residue. Theresidue was treated by silica gel column chromatography(chloroform/methanol=30/1) to give the desired compound (860 mg, yield45%) as a red oil.

¹ H-NMR (CDCl₃) δ: 1.6-2.8 (12H, m), 3.2-3.3 (2H, m), 3.4-3.5 (1H, m),4.46 (2H, s), 4.53 (2H, s), 7.2-8.1 (9H, m).

(2) 2- 3-(4-Benzyloxypiperidino)propyl!-2H-1,2-benzothiazin-4(3H)-one1,1-Dioxide Hydrochloride

In methanol (1 mL) was dissolved 2-3-(4-benzyloxypiperidino)propyl!-2H-1,2-benzothiazin-4(3H)-one1,1-dioxide free base (860 mg, 2 mmol.) obtained in (1). To theresulting solution was added aquoeus 9% hydrochloric acid (1 mL), andthe mixture was placed under reduced pressure to distill the solventoff. The residue was then treated with water and dried to give thedesired compound (700 mg, yield 36%) as an orange amorphous product.

IR (KBr) cm⁻¹ : 3400, 2925, 1690, 1580, 1445, 1335, 1270, 1220, 1170,1120, 1050, 910, 750, 700, 570. ¹ H-NMR (CDCl₃) δ: 1.7-2.2 (6H, m),2.8-3.8 (9H, m), 4.4-4.6 (4H, m), 7.2-8.0 (9H, m).

EXAMPLE 3 3- 3-(4-Benzylpiperidino)propyl!-1H-2,3-benzothiazin-4(3H)-one2,2-Dioxide Fumarate (1) 3-3-(4-Benzylpiperidino)propyl!-1H-2,3-benzothiazin-4(3)-one 2,2-DioxideFree Base

In dry ethanol was dissolved metallic sodium (120 mg, 5.1 mmol.). To thesolution was added 1H-2,3-benzothiazin-4(3H)-one 2,2-dioxide (1.0 g, 5.1mmol.), and the mixture was heated for one hour under refluxing. To thereaction liquid were added 4-benzyl-1-(3-chloropropyl)piperidine (1.28g, 5.1 mol.) and dry ethanol (10 mL), and subsequently the mixture washeated under refluxing for 6 hours. The reaction liquid was placed underreduced pressure to distill the solvent off. The resulting residue wastreated with water, and extracted with ethyl acetate. The ethyl acetateportion was washed with water and an aqueous saturated sodium chloridesolution, and dried over anhydrous sodium sulfate. The dried solutionwas placed under reduced pressure to distill the solvent off, and theresulting resiude was treated by silica gel column chromatography (ethylacetate/hexane=2/1) to give the desired compound (860 mg, yield 40%) asa yellow oil.

¹ H-NMR (CDCl₃) δ: 1.2-1.3 (2H, m), 1.4-1.7 (3H, m), 1.8-2.0 (4H, m),2.3-2.5 (4H, m), 2.89 (2H, d, J=11 Hz), 3.9-4.0 (2H, m), 4.58 (2H, s),7.0-7.4 (6H, m), 7.5-7.6 (2H, m), 8.21 (1H, d, J=8 Hz).

(2) 3- 3-(4-Benzylpiperidino)propyl!-1H-2,3-benzothiazon-4(3H)-one2,2-Dioxide Fumarate

3- 3-(4-Benzylpiperidino)propyl!-1H-2,3-benzothiazin-4(3H)-one2,2-dioxide free base (840 mg, 2.0 mmol.) obtained in (1) was treatedwith fumaric acid (240 mg, 2.0 mmol.) in ethanol (10 mL), to give thedesired compound (830 mg, yield 77%) as a crystalline powder.

M.p.: 154°-155° C., IR (KBr) cm⁻¹ : 3400, 2925, 1680, 1600, 1450, 1430,1350, 1310, 1285, 1195, 1170, 1140, 985, 750, 745, 650. ¹ H-NMR(DMSO-d₆) δ: 1.2-1.3 (2H, m), 1.5-1.6 (3H, m), 1.8-1.9 (2H, m), 2.1-2.2(2H, m), 2.4-2.6 (4H, m), 3.00 (2H, d, J=11 Hz), 3.8-3.9 (2H, m), 5.22(2H, s), 6.53 (2H, s), 7.1-7.3 (5H, m), 7.5-7.8 (3H, m, ArH), 8.05 (1H,d, J=8 Hz).

EXAMPLE 4 2-(3-Morpholino-1-phenylpropyl)-2H-1,2-benzothiazin-3(4H)-one1,1-Dioxide Fumarate

In toluene (7 mL) were suspended 2H-1,2-benzothiazin-3(4H)-one1,1-dioxide (250 mg, 1.3 mmol.), 1-chloro-3-morpholino-1-phenylpropane(340 mg, 1.4 mmol.), potassium carbonate (250 mg, 1.8 mmol.) and acatalytic amount of cupper powder. The suspension was heated for 12hours under refluxing. The reaction liquid was cooled, and theinsolubles were filtered off. The solvent was distilled off to leave aresidue. To the residue were added water and ethyl acetate, and theorganic layer was taken out. The organic solution was washed with waterand an aqueous saturated sodium chloride solution, and dried overanhydrous sodium sulfate. The solvent was distilled off, and theresulting residue was treated by silica gel column chromatogrpahy (ethylacetate) to give the free base of the desired compound (180 mg) as anoil. The free base was treated in the conventional manner to convertinto the desired fumarate.

M.p.: 186°-187° C., IR (KBr) cm⁻¹ : 3400, 1710, 1570, 1450, 1340, 1255,1185, 1130, 1090, 1070, 990, 925, 875, 750, 720, 690, 620, 570. ¹ H-NMR(CD₃ OD) δ: 2.4-3.0 (8H, m), 3.6-3.9 (4H, m), 5.6-5.9 (1H, m), 6.73 (2H,s), 7.1-7.9 (9H, m).

EXAMPLE 5 3-(3-Morpholino-1-phenylpropyl)-2H-1,3-benzothiazin-4(3H)-one1,1-Dioxide Fumarate

In methyl ethyl ketone (5 mL) were suspended2H-1,3-benzothiazin-4(3H)-one 1,1-dioxide (100 mg, 0.518 mmol.),1-chloro-3-morpholino-1-phenylpropane (130 mg, 0.54 mmol.), andpotassium carbonate (180 mg, 1.3 mmol.). The suspension was heatedovernight under refluxing. The reaction liquid was cooled, and theinsolubles were filtered off. The solvent was distilled off to give aresidue. To the residue were added water and ethyl acetate, and theorganic layer was taken out. The organic solution was washed with waterand an aqueous saturated sodium chloride solution, and dried overanhydrous sodium sulfate. The solvent was distilled off, and the residuewas treated by silica gel column chromatography(chloroform/methanol=50/1) to give the free base of the desired compound(70 mg, yield 35%) as an oil.

The free base was treated in the conventional manner to convert into thedesired fumarate.

M.p.: 218° C. (decomp.), IR (KBr) cm⁻¹ : 3400, 1680, 1650, 1440, 1420,1390, 1320, 1270, 1160, 1125, 1110, 1085, 970, 900, 800, 750, 695, 680,530. ¹ H-NMR (CD₃ OD) δ: 2.3-2.5 (2H, m), 2.5-3.3 (6H, m), 3.7-3.9 (4H,m), 4.58 (1H, d, J=16 Hz), 4.88 (1H, d, J=16 Hz), 6.1-6.3 (1H, m), 6.70(2H, s), 7.3-8.4 (9H, m).

EXAMPLES 6 AND 73-(2-Hydroxy-3-morpholinopropyl)-1H-2,3-benzothiazin-4(3H)-one2,2-Dioxide 1/2 Fumarate--Example 63-(2-Ethoxy-3-morpholinopropyl)-1H-2,3-benzothiazin-4(3H)-one2,2-Dioxide Fumarate--Example 7

(1) In dry ethanol (10 mL) was dissolved metallic sodium (23 mg, 1mmol.), and to the solution was added 1H-2,3-benzothiazin-4(3H)-one2,2-dioxide (197 mg, 1 mmol.). The mixture was stirred at 50° C. for 30min. To the reaction solution was added 1-chloro-3-morpholino-2-propanol(198 mg, 1.1 mmol.). The mixture was then heated for 6 hours underrefluxing. The reaction liquid was placed under reduced pressure todistill the solvent off. The resulting residue was treated with 1Nhydrochloric acid and ethyl acetate. The aqueous layer was taken out,and made basic by addition of potassium carbonate. The oil precipitatedand was extracted with ethyl acetate. The ethyl acetate portion waswashed with an aqueous saturated sodium chloride solution, and thendried over anhydrous sodium sulfate. The dried ethyl acetate portion wasplaced under reduced pressure to distill the solvent off. The resultingresidue was treated by silica gel column chromatography(chloroform/methanol=40/1) to give3-(2-hydroxy-3-morpholinopropyl)-1H-2,3-benzothiazin-4(3H)-one2,2-dioxide (215 mg, yield 63%) as a colorless oil, and 3-(2-ethoxy3-morpholinopropyl)-1H-2,3-benzothiazin-4(3H)-one 2,2-dioxide (70mg, yield 20%) as an colorless oil.

3-(2-Hydroxy-3-morpholinopropyl)-1H-2,3-benzothiazin-4(3H)-one2,2-Dioxide

IR (KBr) cm⁻¹ : 3400, 2950, 2910, 2850, 2810, 1680, 1600, 1450, 1350,1305, 1280, 1240, 1195, 1160, 1140, 1115, 1010, 865, 750. ¹ H-NMR(CDCl₃) δ: 2.3-2.7 (6H, m), 3.40 (1H, bs), 3.6-3.8 (4H, m), 4.0-4.2 (3H,m), 4.64 (1H, d, J=16 Hz), 4.69 (1H, d, J=16 Hz), 7.33 (1H, d, J=8 Hz),7.5-7.7 (2H, m), 8.18 (1H, d, J=8 Hz).

3-(2-Ethoxy-3-morpholinopropyl)-1H-2,3-benzothiazin-4(3H)-one2,2-Dioxide

IR (KBr) cm⁻¹ : 2930, 2850, 2800, 1700, 1440, 1405, 1360, 1320, 1295,1260, 1110, 1070, 1000, 860. ¹ H-NMR (CDCl₃) δ: 1.41 (3H, t, J=7 Hz),2.2-2.6 (6H, m), 2.84 (1H, dd, J=6 Hz, 14 Hz), 3.04 (1H, dd, J=2 Hz, 13Hz), 3.6-3.8 (5H, m), 4.39 (2H, q, J=7 Hz), 4.92 (1H, d, J=13 Hz), 4.96(1H, d, J=13 Hz), 7.4-7.5 (1H, m), 7.5-7.6 (2H, m), 7.98 (1H, d, J=8Hz).

(2) 3-(2-Hydroxy-3-Morpholinopropyl)-1H-2,3-benzothiazin-4(3H)-one2,2-Dioxide 1/2 Fumarate (Example 6)

To ethanol (4 mL) were added3-(2-hydroxy-3-morpholinopropyl)-1H-2,3-benzothiazin-4(3H)-one2,2-dioxide (215 mg, 0.63 mmol.) and fumaric acid. (73 mg, 0.63 mmol.).The mixture was heated to give a solution. The solution was kept at roomtemperature. Crystals precipitated and were collected by filtration, togive the desired compound (187 mg, yield 75%) as a white crystallineproduct.

M.p.: 175°-177° C., IR (KBr) cm⁻¹ : 3370, 1690, 1575, 1340, 1285, 1255,1175, 1135, 980. ¹ H-NMR (D₂ O) δ: 3.2-3.5 (6H, m), 3.9-4.2 (6H, m),4.4-4.5 (1H, m), 5.07 (2H, s), 6.52 (1H, s), 7.54 (1H, d, J=8 Hz), 7.67(1H, dd, J=7 Hz, 8 Hz), 7.79 (1H, dd, J=7 Hz, 8 Hz), 8.15 (1H, d, J=8Hz).

(3) 3-(2-Ethoxy-3-morpholinopropyl)-1H-2,3-benzothiazin-4(3H)-one2,2-Dioxide 1/2 Fumarate (Example 7)

To ethanol (2 mL) were added3-(2-ethoxy-3-morpholinopropyl)-1H-2,3-benzothiazin-4(3H)-one2,2-dioxide (73 mg, 0.2 mmol.) and fumaric acid (23 mg, 0.2 mmol.). Themixture was heated to give a solution. The solution was kept at roomtemperature. Crystals precipitated and were collected by filtration, togive the desired compound (64 mg, yield 65%) as a white crystallineproduct.

M.p.: 128°-129° C., IR (KBr) cm⁻¹ : 3400, 1710, 1320, 1300, 1265, 1130,1080, 985, 645. ¹ H-NMR (CD₃ OD) δ: 1.40 (3H, t, J=7 Hz), 2.7-3.1 (18H,m), 3.7-3.9 (4H, m), 3.9-4.0 (1H, m), 4.38 (2H, q, J=7 Hz), 4.98 (2H,s), 6.72 (2H, s), 7.4-7.6 (3H, m), 7.95 (1H, d, J=8 Hz).

EXAMPLE 8 2-(2-Hydroxy-3-morpholinopropyl)-2H-1,2-benzothiazin-4(3H)-one1,1-Dioxide 1/2 fumarate (1)2-(2-Hydroxy-3-morpholinopropyl)-2H-1,2-benzothiazin-4(3H)-one1,1-Dioxide Ethylene Ketal

A suspension of 2H-1,2-benzothiazin-4(3H)-one 1,1-dioxide ethylene ketal(0.48 g, 2 mmol) and 60% sodium hydride (0.08 g, 2 mmol.) in1,2-dimethoxyethane (20 mL) was heated for one hour under refluxing. Theresulting reaction liquid was further heated for 16 hours underrefluxing, after addition of 1-chloro-3-morpholino-2-propanol (0.36 g, 2mmol.). The reaction liquid was placed under reduced pressure to distillthe solvent off. The residue was treated with 1N hydrochloric acid andethyl acetate, and the aqueous layer was taken out. The aquous solutionwas made basic by addition of potassium carbonate, and the precipitatedoil was extracted with ethyl acetate. The extract solution was washedwith an aqueous saturated sodium chloride solution, and dried overanhydrous sodium sulfate. The dried solution was placed under reducedpressure to distill the solvent off. The resulting residue was treatedby silica gel column chromatography (ethyl acetate/methanol=10/1) togive the desired compound (0.54 g, yield 70%) as a colorless oil.

IR (KBr) cm⁻¹ : 3420, 2890, 2810, 1440, 1320, 1270, 1240, 1150, 1110,1050, 1010, 975, 950, 865, 760, 690. ¹ H-NMR (CDCl₃) δ: 2.4-2.7 (6H, m),3.45 (1H, dd, J=6 Hz, 15 Hz), 3.6-3.8 (5H, m), 3.9-4.0 (1H, m), 4.08(2H, s), 4.1-4.3 (4H, m), 7.4-7.6 (3H, m), 7.77 (1H, d, J=8 Hz).

(2) 2-(2-Hydroxy-3-morpholinopropyl)-2H-1,2-benzothiazin-4(3H)-one1,1-Dioxide

In a mixture of methanol (4 mL) and 9% hydrochloric acid (4 mL) wasdissolved 2-(2-hydroxy-3-morpholinopropyl)-2H-1,2-benzothiazin-4(3H)-one1,1-dioxide ethylene ketal (0.38 g, 1 mmol.) obtained in (1). Themixture was then heated for 30 min. under refluxing. The reaction liquidwas placed under reduced pressure to distill the solvent off. Theresidue was treated with an aqueous saturated sodium hydrogen carbonatesolution and ethyl acetate. The organic layer was taken out. The organicsolution was washed with water and then an aqueous saturated sodiumchloride solution, and dried over anhydrous sodium sulfate. The driedsolution was placed under reduced pressure to distill the solvent off,to obtain the desired compound (0.33 g, yield 97%) as a yellow oil.

IR (KBr) cm⁻¹ : 3400, 2920, 2850, 2800, 1695, 1580, 1440, 1330, 1275,1230, 1170, 1110, 1065, 1045, 1005, 920, 860, 760. ¹ H-NMR (CDCl₃) δ:2.3-2.7 (6H, m), 3.13 (1H, dd, J=6 Hz, 14 Hz), 3.3 (1H, bs), 3.45 (1H,dd, J=2 Hz, 14 Hz), 3.6-3.8 (4H, m), 3.8-4.0 (1H, m), 4.63 (1H, d, J=18Hz), 4.71 (1H, d, J=18 Hz), 7.7-7.8 (2H, m), 7.85 (1H, d, J=8 Hz), 8.08(1H, d, J=8 Hz).

(3) 2-(2-Hydroxy-3-morpholinopropyl)-2H-1,2-benzothiazin-4(3H)-one1,1-Dioxide 1/2 Fumarate

In ethanol (6 mL) were dissolved under heating2-(2-hydroxy-3-morpholinopropyl)-2H-1,2-benzothiazin-4(3H)-one1,1-dioxide (0.33 g, 0.97 mmol.) obtained in (2) and fumaric acid (0.11g, 0.97 mmol.). The solution was kept at room temperature. Crystalsprecipitated and were collected by filtration, to give the desiredcompound (0.34 g, yield 65%) as a white crystalline product.

M.p.: 128°-129° C., IR (KBr) cm⁻¹ : 3550, 3450, 1700, 1580, 1560, 1440,1340, 1320, 1275, 1175, 1150, 1135, 1110, 980, 915, 780, 760, 655, 580.¹ H-NMR (CD₃ OD) δ: 2.5-2.8 (6H, m), 3.17 (1H, dd, J=7 Hz, 14 Hz),3.6-3.8 (4H, m), 3.9-4.1 (1H, m), 6.71 (1H, s), 7.7-8.0 (3H, m), 8.07(1H, d, J=8 Hz).

EXAMPLE 9 3-(3-Morpholino-3-phenylpropyl)-1H-2,3-benzothiazin-4(3H)-one2,2-Dioxide 1/2 Fumarate (1)3-(3-Oxo-3-phenylpropyl)-1H-2,3-benzothiazin-4(3H)-one 2,2-Dioxide

1H-2,3-Benzothiazin-4(3H)-one 2,2-dioxide (1 g, 5.08 mmol.) was added toa solution of powdery potassium hydroxide (334 mg, 5.08 mmol.) inmethanol (4 mL). The mixture was then stirred at room temperature for 15min. The solution was placed under reduced pressure to distill thesolvent off to dryness. To the dried product were added3-chloropropiophenone (856 mg, 5.08 mmol.) and dimethylformamide (8 mL).The mixture was heated to 120° C. for 6 hours under stirring. Thereaction liquid was placed under reduced pressure to distill the solventoff. To the resulting residue was added water, and it was extracted withethyl acetate. The extract solution was washed with an aqueous saturatedsodium chloride solution, and dried over anhydrous sodium sulfate. Thedried extract solution was placed under reduced pressure to distill thesolvent off. The resulting oil was treated by silica gel columnchromatography (chloroform) to give the desired compound (1.13 g, yield68%) as a white solid.

¹ H-NMR (CDCl₃) δ: 3.4-3.6 (2H, m), 4.4-4.5 (2H, m), 4.63 (2H, s),7.3-8.3 (9H, m).

(2) 2-(2-Hydroxy-3-phenylpropyl)-1H-2,3-benzothiazin-4(3H)-one2,2-Dioxide

To a suspension of3-(3-oxo-3-phenylpropyl)-1H-2,3-benzothiazin-4(3H)-one 2,2-dioxide (880mg, 2.67 mmol.) obtained in (1) in methanol (35 mL) was added undercooling with ice-water sodium borohydride (310 mg, 8.16 mmol.). Themixture was stirred for 40 min. under the same cooling. The excessivesodium borohydride in the reaction liquid was decomposed by acetic acid(500 mg), and the liquid was placed under reduced pressure to distillthe solvent off. The residue was extracted with ethyl acetate afteraddition of water. The extract solution was washed with an aqueoussaturated sodium chloride solution, and dried over anhydrous sodiumsulfate. The dried extract portion was placed under reduced pressure todistill the solvent off, to give the desired compound (1.02 g) as ayellow oil.

¹ H-NMR (CDCl₃) δ: 2.1-2.3 (2H, m), 4.1-4.3 (2H, m), 4.56 (2H, s),4.7-4.9 (1H, m), 7.3-8.3 (9H, m).

(3) 2-(2-Chloro-3-phenylpropyl)-1H-2,3-benzothiazin-4(3H)-one2,2-Dioxide

In dichloromethane (2 mL) was dissoloved3-(3-hydroxy-3-phenylpropyl)-1H-2,3-benzothiazin-4(3H)-one 2,2-dioxide(1.02 g, 3.08 mmol.) obtained in (2). To the solution was dropwise addedunder ice-cooling a solution of thionyl chloride (420 mg, 3.53 mmol.) indichloromethane (2 mL). The mixture was stirred at room temperature for15 hours. To th reaction liquid was added under ice-cooling an aqueoussaturated sodium hydrogen carbonate solution, and the mixture wasextracted with dichloromethane. The extract portion was washed with anaqeuous saturated sodium chloride solution, and dried over anhydroussodium sulfate. The dried extract portion was placed under reducedpressure to distill the solvent off. The obtained crude product wastreated by silica gel column chromatography (ethyl acetate/n-hexane=1/3)to give the desired compound (690 mg, yield 64%) as a colorless oil.

¹ H-NMR (CDCl₃) δ: 2.5-2.7 (2H, m), 4.1-4.3 (2H, m), 4.53 (2H, s),5.0-5.1 (1H, m), 7.3-8.3 (9H, m).

(4) 3-(3-Morpholino-3-phenylpropyl)-1H-2,3-benzothizin-4(3H)-one2,2-Dioxide 1/2 Fumarate

A mixture of 2-(2-chloro-3-phenylpropyl)-1H-2,3-benzothiazin-4(3H)-one2,2-dioxide (680 mg, 1.95 mmol.) obtained in (3) and morpholine (500 mg,5.75 mmol.) was heated to 110° C. for 6 hours under stirring. Thereaction liquid was extracted with ethyl acetate after addition of anaqueous saturated sodium hydrogen carbonate solution. The extractportion was washed with an aqueous saturated sodium chloride solution,and dried over anhydrous sodium sulfate. The dried extract portion wasplaced under reduced pressure to distill the solvent off. Thus obtainedcrude product was subjected to silica gel column chromatography (ethylacetate/n-hexane=1/1) to give the free base of the desired compound (698mg, yield 89.4%). The free base was warmed to 50° C. after addition offumaric acid (200 mg, 1.74 mmol.) and ethanol (7 mL) to give ahomogeneous solution. The solution was then stirred overnight at roomtemperature. Crystals precipitated and were collected by filtration. Thecollected crystals were dried at 50° C. under reduced pressure to givethe desired compound (606 mg, yield 76%) as a white crystalline product.

M.p.: 130° C., IR (Kr) cm⁻¹ : 3400, 2950, 1670, 1590, 1450, 1330, 1300,1280, 1235, 1190, 1160, 1155, 1100, 1060, 980, 910, 810, 790, 730, 690,550. ¹ H NMR (CD₃ OD) δ: 2.2-2.7 (6H, m), 3.4-3.6 (5H, m), 3.6-4.0 (2H,m), 4.82 (2H, 9), 6.72 (2H, 0), 7.3-8.2 (9H, m).

In the following Examples 10 to 16, the compounds were preparedessentially in the same manner as in Example 1. The prepared compoundsand characteristics thereof are set forth below.

Example 10 2-3-(4-Benzylpiperidino)propyl)-2H-1,2-benzothiazin-4(3H)-one 1,1-DioxideHydrochloride

White crystalline product

IR (KBr) cm⁻¹ : 3455, 2925, 2650, 1700, 1590, 1450, 1340, 1230, 1170,1160, 1120, 950, 920, 790, 770, 750, 700, 580. ¹ H-NMR (DMSO-d₆) δ:1.6-1.8 (3H, m), 1.9-2.1 (2H, m), 2.2-2.3 (2H, m), 2.5-2.7 (4H, m),3.0-3.6 (6H, m), 4.49 (2H, s), 7.0-8.1 (9H, m).

Example 11 2-3-(N-Benzyl-N-butylamino)propyl!-2H-1,2-benzothiazin-4(3H)-one1,1-Dioxide Hydrochloride

Amorphous product

IR (KBr) cm⁻¹ :3370, 2930, 2850, 1690, 1580, 1450, 1340, 1270, 1220,1170, 1120, 1040, 760, 740, 690, 570. ¹ H-NMR (CD₃ OD) δ: 0.97 (3H, t,J=6 Hz), 1.38 (2H, m), 1.75 (2H, m), 1.9-2.4 (2H, m), 2.9-3.4 (6H, m),4.3-4.6 (4H, m), 7.4-7.7 (5H, m), 7.7-8.0 (3H, m), 8.07 (1H, d, J=8 Hz).

Example 12 2-3-(4-Diphenylmethyl-1-piperazinyl)propyl!-2H-1,2-benzothiazin-4(3H)-one1,1-Dioxide Hydrochloride

Pale brown poder

IR (KBr) cm⁻¹ : 3510, 3430, 2810, 2420, 1690, 1580, 1445, 1340, 1275,1170, 1120, 760, 740, 710. ¹ H-NMR (CDCl₃) δ: 1.65 (2H, m), 2.2-2.4 (2H,m), 2.7-3.2 (6H, m), 3.30 (2H, t, J=6 Hz), 3.3-3.6 (2H, m), 4.38 (1H,s), 4.48 (2H, s), 7.2-7.4 (1OH, m), 7.7-7.9 (3H, m), 8.08 (1H, d, J=7Hz), 12.68 (1H, bs).

Example 13 2- 2-(4-Benzylpiperidino)ethyl!-2H-1,2-benzothiazin-4(3H)-one1,1-Dioxide Hydrochloride

M.p.: 198°-201° C., IR (KBr) cm⁻¹ : 3400, 1695, 1580, 1445, 1340, 1270,1230, 1170, 1120, 1040, 760, 750, 700, 570. ¹ H-NMR (CD₃ OD) δ: 1.5-1.6(2H, m), 1.8-1.9 (3H, m), 2.5-2.6 (2H, m), 2.9-3.0 (2H, m), 3.3-3.4 (2H,m), 3.5-3.7 (4H, m), 4.5-4.6 (1H, m), 4.7-4.8 (1H, m), 7.1-7.3 (5H, m),7.8-7.9 (3H, m), 8.0-8.1 (1H, m).

Example 14 2-3-(4-Benzyl-1-piperazinyl)propyl!-2H-1,2-benzothiazin-4(3H)-one1,1-Dioxide Hydrochloride

M.p.: 235°-237° C. (decomp.), IR (KBr) cm⁻¹ : 3400, 2350, 1690, 1580,1440, 1345, 1270, 1230, 1170, 950, 780, 750, 695, 570. ¹ H-NMR (D₂ O) δ:2.0-2.1 (2H, m), 3.2-3.6 (14H, m), 4.35 (2H, s), 7.4-8.1 (9H, m).

Example 15 2- 3-2-(1,2,3,4-Tetrahydroisoquinolyl)!propyl!-2H-1,2-benzothiazin-4(3H)-one1,1-Dioxide Hydrochloride

M.p.: 195°-203° C. (decomp.), IR (KBr) cm⁻¹ : 3400, 2450, 2400, 1690,1590, 1450, 1340, 1270, 1230, 1170, 1120, 1040, 900, 755, 570. ¹ H-NMR(D₂ O) δ: 2.0-2.2 (2H, m), 2.9-3.4 (6H, m), 3.55-3.7 (2H, m), 4.1-4.6(2H, m), 4.60 (2H, s), 7.1-8.0 (9H, m).

Example 16 2- 3-4-(4-Methoxybenzyl)piperidino!propyl!-2H-1,2-benzothiazin-4(3H)-one1,1-Dioxide Hydrochloride

Amorphous product

IR (KBr) cm⁻¹ : 3400, 2925, 2500, 1700, 1610, 1590, 1510, 1445, 1340,1245, 1170, 1130, 1030, 955, 920, 850, 770, 630, 580. ¹ H-NMR (D₂ O) δ:1.65-1.75 (1H, m), 1.8-1.9 (2H, m), 2.3-2.4 (2H, m), 2.56 (2H, d, J=7Hz), 2.56-2.7 (2H, m), 3.31 (2H, t, J=6 Hz), 3.5-3.6 (2H, m), 3.78 (3H,s), 4.49 (2H, s), 6.8-8.1 (8H, m).

In the following Examples 17 to 22, the compounds were preparedessentially in the same manner as in Example 2. The prepared compoundsand characteristics thereof are set forth below.

Example 17 2-(3-Morpholinopropyl)-2H-1,2-benzothiazin-4(3H)-one1,1-Dioxide Fumarate

IR (KBr) cm⁻¹ : 3400, 1690, 1540, 1170, 1120, 980, 770, 640, 570. ¹H-NMR (CD₃ OD) δ: 1.9-2.0 (2H, m), 2.8-3.0 (6H, m), 3.3-3.4 (4H, m),3.9-4.0 (4H, m), 6.72 (2H, s), 7.8-8.1 (4H, m),

Example 182-(3-Diethylamino-1-phenylpropyl)-2H-1,2-benzothiazin-4(3H)-one1,1-Dioxide Hydrochloride

M.p.: 189°-191° C., IR (KBr) cm⁻¹ : 3400, 2925, 2600, 2450, 1690, 1590,1470, 1440, 1400, 1390, 1335, 1275, 1230, 1170, 1135, 1125, 1100, 1075,1050, 1005, 890, 870, 845, 810, 750, 700, 635, 580, 550. ¹ H-NMR (CD₃OD) δ: 1.4-1.5 (6H, m), 2.2-3.4 (8H, m), 4.35 (1H, d, J=19 Hz), 4.66(1H, d, J=19 Hz), 5.0-5.2 (1H, m), 6.8-7.8 (9H, m).

Example 19 2-(1-Phenyl-3-piperidinopropyl)-2H-1,2-benzothiazin-4(3H)-one1,1-Dioxide Hydrochloride

M.p.: 216°-221° C., IR (KBr) cm⁻¹ : 3400, 2500, 1690, 1350, 1180, 710. ¹H-NMR (CDCl₃) δ: 1.5-3.8 (14H, m), 4.1-4.8 (2H, m), 4.9-5.2 (1H, m),6.8-7.8 (9H, m).

Example 20 (A)2-(3-Morpholino-1-phenylpropyl)-2H-1,2-benzothiazin-4(3H)-one1,1-Dioxide Hydrochloride

M.p.: 220° C., IR (KBr) cm⁻¹ : 3400, 2425, 1690, 1590, 1445, 1350, 1330,1280, 1230, 1170, 1130, 1105, 1080, 1040, 1010, 980, 890, 760, 700, 640,580, 550. ¹ H-NMR (CDCl₃) δ: 2.4-2.6 (1H, m), 2.8-3.6 (7H, m), 3.9-4.0(2H, m), 4.2-4.3 (2H, m), 4.35 (1H, d, J=19 Hz), 4.66 (1H, d, J=19 Hz),6.9-7.8 (9H, m).

(B) (-)-2-(3-Morpholino-1-phenylpropyl)-2H-1,2-benzothiazin-4(3H)-one1,1-Dioxide Hydrochloride

2-(3-Morpholino-1-phenylpropyl)-2H-1,2-benzothiazin-4(3H)-one1,1-dioxide hydrochloride (17.48 g, 40.0 mmol.) obtained in (A) wasdissolved in an aqueous saturated sodium hydrogen carbonate solution(300 mL), and then extracted with ethyl acetate. The ethyl acetateportion was washed with water and an aqueous saturated sodium chloridesolution, and dried over anhydrous sodium sulfate. The dried portion wasplaced under reduced pressure to distill the solvent off. To theobtained oil were added methanol (80 mL) and L-(+)-tartaric acid (6.00g, 40.0 mmol.), and the mixture was warmed to 50° C. to give ahomogenous solution. The solution was left to stand at room temperaturefor 5 hours. Crystals precipitated and was recrystallized twice frommethanol to give a diastereomer (5.27 g, 47%) of an optical purity 93.2%e.e. in the form of a white powder. The product (5.26 g) was added to anaqueous saturated sodium hydrogen carbonate solution and extracted withethyl acetate. The ethyl acetate portion was washed with an aqueoussaturated sodium chloride solution, dried over anhydrous sodium sulfate,and placed under reduced pressure to distill the solvent off. To theresidual oil were added ethnaol (20 mL) and then concentratedhydrochloric acid (1 mL). The mixture was allowed to stand overnight.Crystals precipitated and were collected by fitration. The collectedcrystals were washed with ethanol and placed under reduced pressure at40° C. for 3 hours to dryness. Thus, there was obtained the desiredcompound (3.50 g, yield 20%) as a white crystalline product.

M.p.: 238°-240° C., α!²³ =-7.05° (c 0.1, methanol)

(C) (+)-2-(3-Morpholino-1-phenylpropyl)-2H-1,2-benzothiazin-4(3H)-one1,1-Dioxide Hydrochloride

To the mother liquer remaining after the recrystallization step in (B)was added an aqueous saturated sodium hydrogen carbonate solution, andit was extracted with ethyl acetate (100 mL). The ethyl acetate portionwas washed with an aqueous saturated sodium chloride solution (200 mL),dried over anhydrous sodium sulfate, and placed under reduced pressureto distill the solvent off. To thus obtained amorphous product (12.0 g,30.0 mmol.) were added methanol (50 mL) and D-(-)-tartaric acid (4.50 g,30.0 mmol.), and the mixture was warmed to 50° C. to give a homogenoussolution. The solution was allowed to stand overnight at roomtemperature. Crystals precipitated and were recrystallized twice frommethanol to give a diastereomer (7.58 g, 69%) of an optical purity 100%e.e. in the form of a white powder. The product (7.58 g) was added to anaqueous saturated sodium hydrogen carbonate solution and extracted withethyl acetate. The ethyl acetate portion was washed with an aqueoussaturated sodium chloride solution, and dried over anhydrous sodiumsulfate. The drying agent was filtered off. The filtrate was allowed tostand overnight at room temperature after addition of 4N hydrochloricacid gas/ethyl acetate (5 mL). Crystals precipitated and were collectedby fitration. The collected crystals were washed with ethyl acetate, andplaced under reduced pressure at 40° C. for 3 hours to dryness. Thus,there was obtained the desired compound (5.26 g, yield 30%) as a whitecrystalline product.

M.p.: 242°-244° C., α!²³ =+7.44° (c 0.1, methanol)

Example 212-(1-Phenyl-3-thiomorpholinopropyl)-2H-1,2-benzothiazin-4(3H)-one1,1-Dioxide Hydrochloride

M.p.: 224°-227° C., IR (KBr) cm⁻¹ : 3410, 2400, 1690, 1340, 1170, 760. ¹H-NMR (CD₃ OD) δ: 2.3-4.0 (12H, m), 4.4-4.6 (2H, m), 5.0-5.3 (1H, m),6.8-7.8 (9H, m).

Example 22 2-3-Morpholino-1-(4-chlorophenyl)propyl!-2H-1,2-benzothiazin-4(3H)-one1,1-Dioxide Hydrochloride

M.p.: 254° C. (decomp.), IR (KBr) cm⁻¹ : 3400, 2375, 1680, 1580, 1340,1320, 1270, 1230, 1170, 1085, 1005, 890, 815, 740, 585, 550. ¹ H-NMR(CD₃ OD) δ: 2.5-4.4 (14H, m), 5.2-5.4 (1H, m), 6.9-7.8 (8H, m).

In the following Examples 23 to 28, the compounds were preparedessentially in the same manner as in Example 3. The prepared compoundsand characteristics thereof are set forth below.

Example 23 3-(1-Phenyl-3-piperidinopropyl)-1H-2,3-benzothiazin-4(3H)-one2,2-Dioxide 1/2 Fumarate

M.p.: 135°-137° C. (decomp.), IR (KBr) cm⁻¹ : 2930, 1670, 1575, 1440,1350, 1275, 1235, 1190, 1160, 1135, 990, 730. ¹ H-NMR (CDCl₃) δ: 1.4-2.0(6H, m), 2.6-3.2 (8H, m), 4.99 (2H, s), 5.6-5.9 (1H, m), 6.63 (1H, s),6.1-6.7 (8H, m), 6.9-7.1 (1H, m).

Example 24 (A)3-(3-Morpholino-1-phenylpropyl)-1H-2,3-benzothiazin-4(3H)-one2,2-Dioxide Fumarate

M.p.: 144°-145° C., IR (KBr) cm⁻¹ : 3400, 1680, 1450, 1345, 1270, 1170,1130, 980, 910, 870, 800, 730, 690, 640, 560, 500. ¹ H-NMR (CD₃ OD) δ:2.3-3.1 (8H, m), 3.6-3.9 (4H, m), 4.96 (2H, s), 5.7-5.9 (1H, m), 6.64(2H, s), 7.2-7.7 (8H, m, ArH), 7.9-8.1 (1H, m).

(B) (-)-3-(3-Morpholino-1-phenylpropyl)-1H-2,3-benzothiazin-4(3H)-one2,2-Dioxide Fumarate

Water (90 mL) was added to2-(3-morpholino-1-phenylpropyl)-1H-2,3-benzo-thiazin-4(3H)-one2,2-dioxide fumarate (11.33 g, 28.3 mmol.) obtained in (A) asintermediate and D-(-)-tartaric acid (4.24 g, 28.2 mmol.), and themixture was warmed to 80° C. to give a homogenous solution. The solutionwas left to stand overnight at room temperature. Crystals precipitatedand were recrystallized three times from water to give a diastereomer(3.93 g, 25.2%) of an optical purity 98.7% e.e. in the form of a whitepowder. To the product (3.93 g) were added water (100 mL) and 28%aqueous ammonia (3 mL). The mixture was extracted with two portions ofdichloromethane (50 mL). The dichloromethane extract was washed with anaqueous saturated sodium chloride solution, dried over anhydrous sodiumsulfate, and placed under reduced pressure to distill the solvent off.To the residual amorphous product (2.34 g, 5.84 mmol.) was added ethnaol(30 mL). To this mixture was further added a solution of fumaric acid(678 mg, 5.84 mmol.) in ethnaol (20 mL). The resulting mixture was thenstirred overnight. Crystals precipitated and were collected byfitration. The collected crystals were dried at 50° C. for 20 hour.Thus, there was obtained the desired compound (2.6 g, yield 18%) as awhite crystalline product.

M.p.: 160°-163° C., α!²³ =-4.50° (c 0.2, methanol)

(C) (+)-3-(3-Morpholino-1-phenylpropyl)-1H-2,3-benzothiazin-4(3H)-one2,2-Dioxide Fumarate

To the mother liquer remaining after the recrystallization step in (B)was added 28% aqueous ammonia, and it was extracted with three portionsof dichloromethane (100 mL). The dichloromethane extract was washed withan aqueous saturated sodium chloride solution (200 mL), dried overanhydrous sodium sulfate, and placed under reduced pressure to distillthe solvent off. To thus obtained amorphous product (8.5 g, 21.2 mmol.)was added L-(+)-tartaric acid (3.18 g, 22.1 mmol.), and the mixture waswarmed to 80° C. to give a homogenous solution. The solution was allowedto stand overnight at room temperature. Crystals precipitated and wererecrystallized three times from water to give a diastereomer (3.32 g,21.3%) of an optical purity 97.3% e.e. in the form of a white powder. Tothe product (3.32 g) were added water (100 mL) and 28% aqueous ammonia(3 mL), and the mixture was extracted with two portions ofdichloromethane (50 mL). The dichloromethane extract was washed with anaqueous saturated sodium chloride solution (50 mL), dried over anhydroussodium sulfate, and placed under reduced pressure to distill the solventoff. To the resulting amorphous product (2.38 g, 5.94 mmol.) was addedethanol (50 mL). To the mixture were further added a solution of fumaricacid (690 mg, 5.94 mmol.) in ethanol (20 mL). The mixture was stirredovernight at room temperature. Crystals precipitated and were collectedby filtration. The collected crystals were dried at 50° C. for 20 hours.Thus, there was obtained the desired compound (2.35 g, yield 16%) as awhite crystalline product.

M.p.: 163°-164° C., α!²³ =+4.3° (c 0.2, methanol)

Example 253-(3-Diethylamino-1-phenylpropyl)-1H-2,3-benzothiazin-4(3H)-one2,2-Dioxide Fumarate

M.p.: 169°-170° C., IR (KBr) cm⁻¹ : 3400, 1680, 1590, 1540, 1440, 1340,1270, 1230, 1190, 1160, 1140, 980, 800, 740, 720, 690, 640, 550, 500. ¹H-NMR (CD₃ OD) δ: 1.29 (6H, t, J=8 Hz), 2.6-2.8 (2H, m), 3.0-3.4 (6H,m), 5.10 (2H, s), 5.8-5.9 (1H, m), 6.70 (2H, s), 7.2-8.1 (9H, m).

Example 263-(1-Phenyl-3-thiomorpholinopropyl)-1H-2,3-benzothiazin-4(3H)-one2,2-Dioxide Mesylate

M.p.: 231°-233° C. (decomp.), IR (KBr) cm⁻¹ : 1670, 1600, 1350, 1300,1280, 1235, 1205, 1190, 1165, 1145, 1135, 1025, 960. ¹ H-NMR (CDCl₃ /CD₃OD) δ: 2.5-4.2 (12H, m), 2.72 (3H, s), 4.82 (2H, bs), 5.7-5.9 (1H, m),7.1-7.6 (8H, m), 7.9-8.1 (1H, m).

Example 27 3-3-Morpholino-1-(4-chlorophenyl)propyl!-1H-2,3-benzothiazin-4(3H)-one2,2-Dioxide Fumarate

M.p.: 179° C., IR (KBr) cm⁻¹ : 3425, 1680, 1350, 1270, 1160, 980, 730. ¹H-NMR (CD₃ OD) δ: 2.4-3.0 (8H, m), 3.6-3.8 (4H, m), 4.90 (2H, s), 6.68(1H, s), 7.2-8.1 (8H, m).

Example 28 3-(3-Morpholino-2-phenylpropyl)-1H-2,3-benzothiazin-4(3H)-one2,2-Dioxide Fumarate

M.p.: 157°-158° C., IR (KBr) cm⁻¹ : 3400, 2950, 1680, 1600, 1450, 1340,1300, 1280, 1235, 1190, 1160, 1130, 1100, 980, 910, 870, 790, 730, 700,680, 640, 550, 500. ¹ H-NMR (CD₃ OD) δ: 2.6-2.8 (4H, m), 2.9-3.0 (1H,m), 3.0-3.1 (1H, m), 3.5-3.7 (5H, m), 4.0-4.1 (1H, m), 4.2-4.3 (1H, m),4.6 (1H, d, J=6 Hz), 4.78 (1H, d, J=6 Hz), 6.71 (2H, s), 7.2-8.1 (9H,m).

Example 29 2-(3-Morpholino-3-phenylpropyl)-1H-1,2-benzothiazin-4(3H)-one1,1-Dioxide Hydrochloride

The above-mentioned compound was prepared essentially in the same manneras in Example 9.

M.p.: 214°-216° C. (decomp.), IR (KBr) cm⁻¹ : 3550, 3380, 2580, 2550,2470, 1695, 1455, 1340, 1280, 1170, 1125, 760, 700, 575. ¹ H-NMR (D₂ O)δ: 2.5-2.7 (2H, m), 3.1-3.6 (6H, m), 3.8-4.1 (4H, m), 4.45 (1H, dd, J=4Hz, 12 Hz), 7.5-7.6 (5H, m), 7.82 (1H, d, J=8 Hz), 7.92 (1H, dd, J=8 Hz,8 Hz), 8.01 (1H, d, J=8 Hz).

Example 30 2-(3-Chloropropyl)-2H-1,2-benzothiazin-4(3H)-one 1,1-Dioxide

A mixture of 2-(3-chloropropyl)-2H-1,2-benzothiazin-4(3H)-one1,1-dioxide ethylene ketal (5.0 g, 15.7 mmol.), 3N aqueous hydrochloricacid (30 mL) and methanol (30 mL) was heated under refluxing for 20 min.Methanol was distilled off under reduced pressure. To the residue wasadded water (30 mL), and the mixture was extracted with ethyl ether. Theethyl ether portion was washed with an aqueous saturated sodium chloridesolution, dried over anhydrous sodium sulfate, and placed under reducedpressure to distill the solvent off, to give the desired compound (4.19g, 100%) as a yellow oil.

¹ H-NMR (CDCl₃) δ: 2.0-2.1 (2H, m), 3.36 (2H, t, J=6 Hz), 3.65 (2H, t,J=6 Hz), 4.46 (2H, s), 7.7-8.1 (4H, m).

Example 31 2- 3-(2,3-Dihydro-1H-benzde!isoquinolin-2-yl)propyl!-2H-1,2-benzothiazin-4(3H)-one 1,1-DioxideHydrochloride

A mixture of 2-(3-chloropropyl)-2H-1,2-benzothiazin-4(3H)-one1,1-dioxide (324 mg, 1.18 mmol) obtained in Example 30, 3N aqueoushydrouchloric acid (30 mL) and methanol (30 mL) was heated to reflux for20 min. The mixture was then placed under reduced pressure to distillmethanol off. To the residue was added water, and the aqueous mixturewas subjected to extraction with diethyl ether. The diethyl etherportion was washed with an aqueous saturated sodium chloride solution,dried over anhydrous sodium sulfate, and placed under reduced pressureto distill the solvent off. The resulting crude product was subjected tosilica gel column chromatography. Its eluate at ethyl acetate/n-hexane(1/1) gave a red oil (200 mg, 41.7%). The oil was dissolved in methanol(1 mL), made acidic by 3N hydrochloric acid, and placed under reducedpressure to distill methanol off. The residue was allowed to stand afteraddition of water, to give the desired compound (133 mg, 61.0%) as anorange solid.

Free base

¹ H-NMR (CDCl₃) δ: 1.9-2.0 (2H, m), 2.70 (2H, t, J=7 Hz), 3.32 (2H, t,J=7 Hz), 3.95 (4H, s), 4.45 (2H, s), 7.1-8.1 (10H, m).

Hydrochloride (desired compound)

¹ H-NMR (CD₃ OD) δ: 2.2-2.3 (2H, m), 3.3-3.4 (2H, m), 3.4-3.5 (2H, m),4.6-5.0 (6H, m), 7.5-8.1 (10H, m). IR (KBr) cm⁻¹ : 3350, 1685, 1585,1430, 1335, 1270, 1250, 1225, 1170, 1120, 1105, 1040, 990, 900, 820,790, 770, 735, 680, 640, 570. M.p.: above 220° C. (decomp.).

Example 32 2-3-(4-Cyano-4-phenylpiperidino)propyl!-2H-1,2-benzothiazin-4(3H)-one1,1-Dioxide Fumarate

2-(3-Chloropropyl)-2H-1,2-benzothiazin-4(3H)-one 1,1-dioxide (485 mg,1.77 mmol.) obtained in Example 30 and 4-cyano-4-phenylpiperidine (330mg, 77 mmol.) were treated essentially in the same manner as in EXample31 to give a free acid of the desired compound (411 mg, 56.7%) and itsfumarate (300 mg, 56.9%).

Free base

¹ H-NMR (CDCl₃) δ: 1.75-1.85 (2H, m), 2.0-2.2 (4H, m), 2.4-2.6 (4H, m),2.9-3.0 (2H, m), 3.29 (2H, t, J=7 Hz), 4.47 (2H, s), 7.2-8.1 (9H, s).

Fumarate (desired compound)

¹ H-NMR (CD₃ OD) δ: 1.7-1.8 (2H, m), 1.9-2.1 (4H, m), 2.9-3.0 (2H, m),3.15-3.25 (2H, m), 4.56 (2H, s), 6.63 (2H, s), 7.3-8.0 (9H, m). IR (KBr)cm⁻¹ : 3400, 1710, 1690, 1580, 1340, 1295, 1170, 910, 750, 570. M.p.:145°-150° C.

Example 33 2-(3-Chloro-1-phenylpropyl)-2H-1,2-benzothiazin-4(3H) -one1,1-Dioxide

2-(3-Chloro-1-phenylpropyl)-2H-1,2-benzothiazin-4(3H)-one 1,1-dioxideethylene ketal (500 mg, 27 mmol.) which was obtained essentially in thesame manner as in Example 1-(1) was suspended in a mixture of ethanol (3mL) and concentrated hydrochloric acid (1 mL), and heated to reflux for2 hours. The reaction liquid was placed under reduced pressure todistill ethanol off, and extracted with ethyl acetate after addition ofwater. The ethyl acetate portion was washed with an aqueous saturatedsodium chloride solution, dried over anhydrous sodium sulfate, andplaced under reduced pressure to distill the solvent off. There wasobtained the desired compound (380 mg, 85.6%) as an orange oil.

¹ H-NMR (CDCl₃ : 400 MHz) δ: 2.3-2.4 (1H, m), 2.5-2.6 (1H, m), 3.5-3.7(2H, m), 4.13 (1H, d, J=19 Hz), 4.60 (1H, d, J=19 Hz), 5.4-5.5 (1H, m),6.9-7.8 (9H, m).

Example 34 2-3-(4-Cyano-4-phenylpiperidino)-1-phenylpropyl!-2H-1,2-benzothiazin-4(3H)-one1,1-Dioxide Fumarate

4-Cyano-4-phenylpiperidine (236 mg, 1.06 mmol.) was dissolved in water(3 mL), made alkaline by an aqueous saturated sodium hydrogen carbonatesolution, and extracted with dichloromethane. The dichloromethaneportion was dried over anhydrous sodium sulfate, and placed underreduced pressure to distill the solvent off, to give an oil. The oil and2-(3-chloro-1-phenylpropyl)-2H-1,2-benzothiazin-4(3H)-one 1,1-dioxideobtained in Example 33 were treated essentially in the same manner as inExample 31, to give a free base of the desired compound (160 mg, 30.2%)and its fumarate (37 mg, 18.8%, orange solid).

Free base

¹ H-NMR (CDCl₃, 400 MHz) δ: 2.0-2.2 (6H, m), 2.5-2.6 (4H, m), 2.9-3.1(2H, m), 4.18 (1H, d, J=19 Hz), 4.58 (1H, d, J=19 Hz), 5.3-5.4 (1H, m),6.9-7.8 (9H, m).

Fumarate (desired compound)

¹ H-NMR (CDCl₃, 400 MHz) δ: 2.1-2.3 (6H, m), 2.5-2.6 (4H, m), 2.9-3.1(2H, m), 3.40 (1H, s), 4.20 (1H, s), 5.3-5.4 (1H, m), 7.0-7.8 (9H, m).IR (KBr) cm⁻¹ : 3400, 1690, 1590, 1450, 1335, 1280, 1230, 1170, 1080,980, 765, 700, 640, 590, 550. M.p.: 188°-190° C.

Example I 2-1-Phenyl-3-(1-pyrrolidinyl)!propyl-1,2-benzisothiazol-3(2H)-one1,1-Dioxide Fumarate (1) 2-1-Phenyl-3-(1-pyrrolidinyl)!propyl-1,2-benzisothiazol-3(2H)-one1,1-Dioxide

In dimethylformamide (DMF) (8 mL) were suspended 1-(3-chloro-3-phenyl)propyl!pyrrolidine hydrochloride (1.04 g, 4.00mmol.), anhydrous potassium carbonate (1.11 g, 8.03 mmol.), andsaccharin (733 mg, 4.00 mmol). The suspension was heated under stirringto 100° C. for 3 hours to carry out a reaction. The reaction liquid wascooled to room temperature, and placed under reduced pressure to distillDMF off. To the residue were added water and ethyl acetate, and theorganic layer was taken out. The organic portion was washed with anaqueous saturated sodium chloride solution, dried over anhydrous sodiumsulfate, and placed under reduced pressure to distill the solvent off.The residue was subjected to silica gel column chromatography(chloroform/methanol=30/1) to obtain 438 mg of the desired compound(yield 30%) as a pale yellow oil.

IR (KBr) cm⁻¹ : 2950, 2780, 1720, 1455, 1330, 1290, 1250, 1180, 750,695, 670. ¹ H-NMR (CDCl₃) δ: 1.4-1.2 (4H, m), 2.2-3.1 (8H, m), 5.39 (1H,t, J=7 Hz), 7.1-8.0 (9H, m).

(2) 2- 1-Phenyl-3-(1-pyrrolidinyl)!propyl-1,2-benzisothiazol-3(2H)-one1,1-Dioxide Fumarate

A solution of fumaric acid (128 mg, 1.10 mmol.) in hot ethanol (4 mL)was added to a solution of 2-1-phenyl-3-(1-pyrrolidinyl)!propyl-1,2-benzisothiazol-3(2H)-one1,1-dioxide (408 mg, 1.10 mmol). The obtained solution was placed underreduced pressure to distill the solvent off. The residue wasrecrystallized from ethanol/ether, to give 360 mg of the desiredcompound (yield 67%) as a white crystalline product.

IR (KBr) cm⁻¹ : 2910, 2640, 2600, 2560, 2470, 1675, 1595, 1465, 1445,1380, 1330, 1310, 1220, 960, 750, 690. ¹ H-NMR (CDCl₃ /CD₃ OD=6/1) δ:2.92 (6H, s), 3.3-3.8 (4H, m), 7.2-7.7, 7.8-8.1 (5H, m).

Example II2-(1-Phenyl-3-thiomorpholino)propyl-1,2-benzisothiazol-3(2H)-one1,1-Dioxide Fumarate (1) 1-Bromo-3-chloro-1-phenylpropane

3-Chloro-1-phenylpropane (3.09 g, 20 mmol.), N-bromosuccinimide (3.56 g,20 mmol.), benzoyl peroxide (catalytic amount), and carbon tetrachloride(30 mL) were mixed, and the resulting mixture was heated to reflux for15 min while it was exposed to a light of 100V/100 W, to perform areaction. Insolubles were filtered off. The reaction liquid was washedwith an aqueous saturated sodium hydrogen carbonate solution and anaqueous saturated sodium chloride solution, dried over anhydrous sodiumsulfate, and placed under reduced pressure to distill the solvent off,to give 4.58 g of the desired compound (yield 98%) as an oil.

¹ H-NMR (CDCl₃) δ: 2.1-2.9 (2H, m), 3.3-3.9 (2H, m), 5.16 (1H, dd, J=7Hz, 10 Hz), 7.1-7.5 (5H, m).

(2) 2-(3-Chloro-1-phenyl)propyl-1,2-benzisothiazol-3(2H)-one 1,1-Dioxide

In DMF (10 mL) were suspended 1-bromo-3-chloro-1-phenylpropane (1.00 g,4.28 mmol.), saccharin (780 mg, 4.3 mmol), and potassium carbonate (600mg, 4.4 mmol.). The suspension was heated under stirring to 100° C. for3 min. to carry out a reaction. The reaction liquid was placed underreduced pressure to distill DMF off. To the residue were added water andethyl acetate, and the organic layer was taken out. The organic portionwas washed with water and an aqueous saturated sodium chloride solution,dried over anhydrous sodium sulfate, and placed under reduced pressureto distill the solvent off. The residue was subjected to silica gelcolumn chromatography (hexane/ethyl acetate=2/1) to obtain 440 mg of thedesired compound (yield 31%) as an oil.

IR (KBr) cm⁻¹ : 1720, 1590, 1450, 1390, 1325, 1290, 1250, 1180, 1125,1060, 1010, 940, 850, 760, 750, 695, 670, 580, 560, 535, 510. ¹ H-NMR(CDCl₃) δ: 2.5-3.2 (2H, m), 3.3-3.8 (2H, m), 5.46 (1H, t, J=8 Hz),7.1-8.0 (9H, m).

(3) 2-(1-Phenyl-3-thiomorpholino)propyl-1,2-benzisothiazol-3(2H)-one1,1-Dioxide

2-(3-Chloro-1-phenyl)propyl-1,2-benzisothiazol-3(2H)-one 1,1-dioxide(1.01 g, 3 mmol.) and thiomorpholine (0.62 g, 6 mmol.) were mixed witheach other. The mixture was heated to 110° C. under stirring for 6hours, to perform a reaction. The reaction liquid was cooled to roomtemperature. To the cooled liquid were added 2N-hydrochloric acid andethyl acetate, and the aqueous layer was taken out. The aqueous portionwas made alkaline by addition of an aqueous saturated sodium hydrogencarbonate solution. An oil precipitated, which was then extracted withethyl acetate. The ethyl acetate portion was washed with an aqueoussaturated sodium chloride solution, dried over anhydrous sodium sulfate,and placed under reduced pressure to distill the solvent off. Theresidue was subjected to silica gel column chromatography (hexane/ethylacetate=2/1) to obtain 420 mg of the desired compound (yield 35%) as acolorless oil.

IR (KBr) cm⁻¹ : 2800, 1720, 1450, 1330, 1285, 1255, 1180, 1130, 750,700, 580. ¹ H-NMR (CDCl₃) δ: 2.3-2.9 (12H, m), 5.3-5.4 (1H, m), 7.2-7.4(3H, m), 7.6-7.7 (2H, m), 7.7-7.8 (2H, m), 7.84 (1H, dd, J=1 Hz, 8 Hz),7.94 (1H, dd, J=1 Hz, 7 Hz).

(4) 2-(1-Phenyl-3-thiomorpholino)propyl-1,2-benzisothiazol-3(2H)-one1,1-Dioxide Fumarate

A solution of fumaric acid (120 mg, 1 mmol.) in hot ethanol (12 mL) wasadded to a solution of2-(1-phenyl-3-thiomorpholino)propyl-1,2-benzisothiazol-3(2H)-one1,1-dioxide (400 mg, 1 mmol.) in ethanol (20 mL). The mixture wasstirred at room temperature. Insolubles precipitated and were collectedby filtration and recrystallized from water, to give 325 mg of thedesired compound (yield 64%) as a white crytalline powder.

M.p.: 187°-189° C., IR (KBr) cm⁻¹ : 1720, 1335, 1290, 1250, 1175. ¹H-NMR (D₂ O) δ: 2.8-4.0 (12H, m), 5.4-5.6 (1H, m), 6.61 (2H, s), 7.4-7.5(3H, m), 7.6-7.7 (2H, m), 7.9-8.1 (4H, m).

In the following Examples III to XX, the compounds were preparedessentially in the same manner as in Example I. The prepared compoundsand characteristics thereof are set forth below.

Example III 2-(2-Morpholino-1-phenyl)ethyl-1,2-benzisothiazol-3(2H)-one1,1-Dioxide Mesylate

M.p.: 240°-241° C. (decomp.), IR (KBr) cm⁻¹ : 1745, 1325, 1290, 1260,1220, 1180, 1160, 1040, 555. ¹ H-NMR (CD₄ OD) δ: 2.64 (3H, s), 3.2-4.2(8H, m), 3.97 (1H, dd, J=4 Hz, 14 Hz), 5.91 (1H, dd, J=4 Hz, 12 Hz),7.3-7.7 (5H, m), 7.9-8.2 (4H, m).

Example IV 2-(4-Morpholino-1-phenyl)butyl-1,2-benzisothiazol-3(2H)-one1,1-Dioxide Fumarate

M.p.: 175°-177° C. (decomp.), IR (KBr) cm⁻¹ : 3450, 1720, 1635, 1330,1290, 1255, 1180. ¹ H-NMR (CD₃ OD) δ: 1.8-2.0 (1H, m), 2.3-2.5 (1H, m),2.6-2.8 (1H, m), 3.0-4.2 (10H, m), 5.45 (1H, dd, J=7 Hz, 9 Hz), 6.64(2H, s), 7.4-7.5 (3H, m), 7.6-7.7 (2H, m), 7.9-8.0 (2H, m), 8.04 (1H, d,J=8 Hz), 8.07 (1H, d, J=8 Hz).

Example V 2-(1-Phenyl-3-piperidino)propyl-1,2-benzisothiazol-3(2H)-one1,1-Dioxide Fumarate

M.p. 182° C., IR (KBr) cm⁻¹ : 3440, 2940, 1730, 1595, 1445, 1390, 1325,1295, 1255, 1195, 985, 750, 700, 675. ¹ H-NMR (DMSO-d₆) δ: 1.2-1.7 (6H,m), 2.2-3.0 (8H, m), 5.36 (1H, t, J=8 Hz), 6.55 (2H, s), 7.3-8.2 (9H,m), 10.0 (2H, brs).

Example VI 2-3-(Perhydroazepin-1-yl)-1-phenyl!propyl-1,2-benzisothiazol-3(2H)-one1,1-Dioxide Fumarate

IR (KBr) cm⁻¹ : 3410, 2920, 2620, 1720, 1320, 1285, 1250, 1180, 975,740. ¹ H-NMR (CD₃ OD) δ: 1.5-2.1 (8H, s), 2.4-3.5 (8H, m), 5.1-5.5 (1H,m), 6.67 (2H, s), 7.1-8.1 (9H, m).

Example VII 2- (3-(4-methylpiperidino)-1-phenyl!propyl-1,2-benzisothiazol-3(2H)-one1,1-Dioxide Fumarate

M.p.: 177°-178° C., IR (KBr) cm⁻¹ : 3400, 3000, 2950, 2750, 2550, 1720,1695, 1630, 1590, 1530, 1450, 1390, 1330, 1290, 1250, 1200, 1180, 1050,1000, 985, 970, 950, 920, 790, 750, 695, 670, 630, 580, 550, 505. ¹H-NMR (CD₃ OD) δ: 1.00 (3H, d, J=6 Hz), 1.0-2.0 (5H, m), 2.5-3.7 (8H,m), 5.2-5.4 (1H, m), 7.2-8.1 (9H, m).

Example VIII 2-3-(4-Carbamoylpiperidino)-phenyl!propyl-1,2-benzisothiazol-3(2H)-one1,1-Dioxide Fumarate

M.p.: 178°-180° C., IR (KBr) cm⁻¹ : 3420, 1725, 1670, 1610, 1325, 1290,1265, 1180, 980, 750, 640, 580. ¹ H-NMR (D₂ O) δ: 1.8-2.2, 2.6-3.8 (13H,m), 5.50 (1H, dd, J=7 Hz, 9 Hz), 6.67 (2H, s), 7.4-7.5 (3H, m), 7.6-7.7(2H, m), 7.9-8.1 (4H, m).

Example IX 2-(3-Morpholino-1-pheny)propyl-1,2-benzisothiazol-3(2H)-one1,1-Dioxide Fumarate

M.p.: 159° C., IR (KBr) cm⁻¹ : 3425, 2855, 1720, 1655, 1610, 1495, 1450,1370, 1330, 1290, 1270, 1250, 1180, 1130, 1095, 1060, 980, 900, 870,790, 750, 690, 675, 640, 610, 580, 550, 510. ¹ H-NMR (CD₃ OD) δ: 2.4-3.0(8H, m), 3.6-3.8 (4H, m), 5.2-5.4 (1H, m), 6.66 (2H, s), 7.2-8.1 (9H,m).

Example X 2-3-(4-Ethyl-1-piperazinyl)-1-pheny!propyl-1,2-benzisothiazol-3(2H)-one1,1-Dioxide Difumarate

M.p.: above 200° C. (decomp.), IR (KBr) cm⁻¹ : 3400, 1720, 1320, 1290,1250, 1180, 980, 750, 640. ¹ H-NMR (CD₃ OD) δ: 1.28 (3H, t), 2.4-3.2(14H, m), 5.2-5.4 (1H, m), 6.66 (4H, s), 7.3-8.1 (9H, m).

Example XI 2-3-(4-Acetyl-1-piperazinyl)-1-pheny!propyl-1,2-benzisothiazol-3(2H)-one1,1-Dioxide Fumarate

M.p.: 129°-130° C., IR (KBr) cm⁻¹ : 3400, 3000, 2950, 2575, 1720, 1640,1410, 1325, 1290, 1250, 1180, 980, 750, 670, 640, 580, 500. ¹ H-NMR (CD₃OD) δ: 2.04 (3H, s), 2.4-2.9 (8H, m), 3.4-3.7 (4H, m), 5.2-5.5 (1H, m),6.68 (2H, s), 7.2-8.1 (9H, m).

Example XII 2- 1-Phenyl-3-4-(2-pyrimidinyl)-1-piperazinyl!propyl-1,2-benzisothiazol-3(2H)-one1,1-Dioxide Hydrochloride

IR (KBr) cm⁻¹ : 3470, 1725, 1620, 1580, 1550, 1440, 1330, 1290, 1250,1180, 580. ¹ H-NMR (D₂ O) δ: 2.8-4.0 (12H, m), 5.55 (1H, dd, J=7 Hz, 9Hz), 6.87 (1H, t, J=5 Hz), 7.4-7.5 (3H, m), 7.6-7.7 (2H, m), 7.9-8.1(4H, m), 8.44 (2H, d, J=5 Hz).

Example XIII 2-1-(4-Chlorophenyl)-3-piperidino!propyl-1,2-benzisothiazol-3(2H)-one1,1-Dioxide Fumarate

M.p.: 193°-194° C. (decomp.), IR (KBr) cm⁻¹ : 3400, 2945, 1720, 1650,1590, 1485, 1455, 1330, 1280, 1240, 1175, 1120, 1085, 1055, 1005, 980,830, 780, 745, 720, 645, 630, 600, 575, 550, 520, 505. ¹ H-NMR (CD₃ OD)δ: 1.4-2.0 (6H, m), 3.0-3.3 (8H, m), 5.2-5.4 (1H, m), 6.62 (2H, s),7.2-8.1 (8H, m).

Example XIV 2-1-(4-chlorophenyl)-3-morpholino!propyl-1,2-benzisothiazol-3(2H)-one1,1-Dioxide Fumarate

M.p.: 189°-190° C., IR (KBr) cm⁻¹ : 3425, 1725, 1610, 1590, 1490, 1450,1400, 1325, 1280, 1250, 1170, 1125, 1090, 1060, 1010, 975, 920, 870,840, 800, 780, 740, 715, 670, 640, 615, 580, 570, 505. ¹ H-NMR (CD₃ OD)δ: 2.3-3.0 (8H, m), 3.5-3.8 (4H, m), 5.2-5.4 (1H, m), 6.66 (2H, s),7.2-7.7 (4H, m), 7.8-8.1 (5H, m).

Example XV 2-1-(4-Methoxyphenyl)-3-piperidino!propyl-1,2-benzisothiazol-3(2H)-one1,1-Dioxide Fumarate

M.p.: 173°-176° C. (decomp.), IR (KBr) cm⁻¹ : 3410, 2950, 2510, 1735,1610, 1510, 1325, 1290, 1245, 1180, 980, 745. ¹ H-NMR (CD₃ OD) δ:1.4-2.1 (6H, m), 2.4-3.4 (8H, m), 3.79 (3H, s), 5.0-5.4 (1H, m), 6.73(2H, s), 6.7-7.0, 7.3-8.1 (8H, m).

Example XVI6-Chloro-2-(4-phenyl-3-piperidino)propyl-1,2-benzisothiazol-3(2H)-one1,1-Dioxide Fumarate

M.p.: 212°-214° C. (decomp.), IR (KBr) cm⁻¹ : 3400, 2940, 1730, 1585,1320, 1260, 1240, 1175, 980. ¹ H-NMR (DMSO-d₆) δ: 1.1-1.6 (6H, m),2.0-2.9 (8H, m), 5.33 (H, t, J=7 Hz), 6.57 (2H, s), 7.1-7.6 (5H, m),7.9-8.0 (2H, m), 8.3-8.4 (40, m).

Example XVII6-Chloro-2-(3-morpholino-1-phenyl)propyl-1,2-benzisothiazol-3(2H)-one1,1-Dioxide Fumarate

M.p.: 197°-198° C., IR (KBr) cm⁻¹ : 3425, 1725, 1585, 1490, 1450, 1400,1390, 1320, 1260, 1240, 1170, 1125, 1090, 975, 865, 830, 800, 750, 690,655, 630, 580, 520, 450. ¹ H-NMR (CD₃ OD) δ: 2.3-3.0 (8H, m), 3.5-3.8(4H, m), 5.2-5.4 (4H, m), 6.66 (2H, s), 7.2-7.7 (5H, m), 7.9-8.2 (3H,m).

Example XVIII6-Methoxy-2-(1-phenyl-3-piperidino)propyl-1,2-benzisothiazol-3(2H)-one1,1-Dioxide Fumarate

M.p.: 199°-201° C. (decomp.), IR (KBr) cm⁻¹ : 3420, 2950, 1725, 1600,1580, 1490, 1320, 1265, 1170, 980. ¹ H-NMR (DMSO-d₆) δ: 1.1-1.7 (6H, m),2.0-2.9 (8H, m), 3.96 (3H, s), 5.32 (1H, t, J=7 Hz), 6.57 (2H, s),7.2-8.0 (8H, m).

Example XIX6-Methoxy-2-(3-morpholino-1-phenyl)propyl-1,2-benzisothiazol-3(2H)-one1,1-Dioxide Fumarate

M.p.: 196°-198° C. (decomp.), IR (KBr) cm⁻¹ : 1725, 1605, 1580, 1490,1320, 1270, 1170. ¹ H-NMR (D₂ O) δ: 2.7-4.3 (12H, m), 3.97 (3H, s), 5.50(1H, dd, J=6 Hz, 9 Hz), 6.59 (2H, s), 7.4-7.5 (4H, m), 7.6-7.7 (3H, m),7.94 (1H, d, J=1 Hz).

Example XX4-Chloro-2-(3-piperidino-1-phenyl)propyl-1,2-benzisothiazol-3(2H)-one1,1-Dioxide Fumarate

M.p.: 208° C., IR (KBr) cm⁻¹ : 3425, 3050, 2950, 2675, 2525, 1720, 1570,1445, 1395, 1340, 1250, 1210, 1180, 1150, 980, 930, 790, 760, 690, 660,635, 580, 560, 520, 470. ¹ H-NMR (CD₃ OD) δ: 1.3-2.1 (6H, m), 2.5-3.4(8H, m), 5.2-5.5 (1H, m), 6.64 (2H, s), 7.2-8.0 (3H, m).

In the following Examples XXI to XXVIII, the compounds were preparedessentially in the same manner as in Example II. The prepared compoundsand characteristics thereof are set forth below.

Example XXI2-(1-Phenyl-3-thiomorpholino)propyl-1,2-benzisothiazol-3(2H)-one1,1,S-trioxide Fumarate

M.p.: 178°-180° C. (decomp.), IR (KBr) cm⁻¹ : 3420, 1735, 1395, 1320,1290, 1250, 1180, 1020, 1000, 980, 925, 760, 740, 640, 580. ¹ H-NMR (D₂O) δ: 2.8-3.0 (1H, m), 3.0-3.4 (7H, m), 3.6-3.9 (4H, m), 5.51 (1H, t,J=8 Hz), 6.66 (2H, s), 7.4-7.5 (3H, m), 7.6-7.7 (2H, m), 7.8-8.0 (3H,m), 8.02 (1H, d, J=7 Hz).

Example XXII2-(1-Phenyl-3-thiomorpholino)propyl-1,2-benzisothiazol-3(2H)-one1,1,S,S-tetraoxide Mesylate

Amorphous

IR (KBr) cm⁻¹ : 3420, 1720, 1320, 1290, 1250, 1180, 1130. ¹ H-NMR (D₂ O)δ: 2.8-3.2 (2H, m), 2.82 (3H, s), 3.4-3.6 (2H, m), 3.6-3.8 (4H, m),3.8-4.1 (4H, m), 5.52 (1H, dd, 7=7 Hz, 9 Hz), 7.4-7.6 (3H, m), 7.6-7.7(2H, m), 7.8-8.1 (4H, m).

Example XXIII 2-3-(2-Methylthiomorpholino)-1-phenyl!propyl-1,2-benzisothiazol-3(2H)-one1,1-Dioxide Fumarate

M.p.: 170°-178° C., IR (KBr) cm⁻¹ : 3400, 1730, 1330, 1290, 1250, 1180,970, 750. ¹ H-NMR (CDCl₃) δ: 1.12, 1.16 (3H, d, J=8 Hz), 2.2-3.2 (11H,m), 5.2-5.4 (1H, m), 6.72 (2H, s), 7.2-8.0 (9H, m).

Example XXIV 2-3-(3-Methylthiomorpholino)-1-phenyl!propyl-1,2-benzisothiazol-3(2H)-one1,1-Dioxide Fumarate

M.p.: 175°-177° C., IR (KBr) cm⁻¹ : 3400, 1730, 1450, 1380, 1330, 1290,1250, 1180, 970, 750, 690, 670, 640, 580, 540, 510. ¹ H-NMR (CD₃ OD) δ:1.1-1.3 (3H, m), 2.3-3.7 (11H, m), 5.2-5.4 (1H, m), 6.68 (2H, s),7.2-8.1 (9H, m).

Example XXV 2-3-(2,2-Dimethylthiomorpholino)-1-phenyl!propyl-1,2-benzisothiazol-3(2H)-one1,1-Dioxide Mesylate

Amorphous

IR (KBr) cm⁻¹ : 3400, 1730, 1330, 1290, 1240, 1180, 1060, 785, 560, 540.¹ H-NMR (D₂ O) δ: 1.35 (3H, s), 1.55 (3H, s), 2.8-3.4 (8H, m), 2.84 (3H,s), 3.5-3.6 (1H, m), 3.8-3.9 (1H, m), 5.4-5.6 (1H, m), 7.4-7.5 (3H, m),7.6-7.7 (2H, m), 7.8-8.1 (4H, m).

Example XXVI 2-3-(2,6-Dimethylthiomorpholino)-1-phenyl!propyl-1,2-benzisothiazol-3(2H)-one1,1-Dioxide Fumarate

M.p.: 167° C., IR (KBr) cm⁻¹ : 3400, 1730, 1690, 1555, 1445, 1380, 1320,1280, 1250, 1180, 1050, 980, 750, 695, 670, 640, 580, 510. ¹ H-NMR (CD₃OD) δ: 1.12 (3H, dd, J=4 Hz, 8 Hz), 1.30 (3H, dd, J=4 Hz, 8 Hz), 2.2-3.4(8H, m), 5.2-5.5 (1H, m), 6.66 (2H, s), 7.2-8.1 (9H, m).

Example XXVII 2-1-Phenyl-3-(2-phenylthiomorpholino)!propyl-1,2-benzisothiazol-3(2H)-one1,1-Dioxide Mesylate

Amorphous

IR (KBr) cm⁻¹ : 3420, 1720, 1450, 1330, 1290, 1250, 1180, 1060, 1035,750, 695, 580. ¹ H-NMR (CD₃ OD) δ: 2.71 (3H, s), 2.6-3.1 (2H, m),3.2-3.7 (6H, m), 3.8-4.0 (2H, m), 4.3-4.4 (1H, m), 5.3-5.4 (1H, m),7.3-7.7 (1OH, m), 7.9-8.1 (4H, m).

Example XXVIII 2-1-(4-Fluorophenyl)-3-thiomorpholino!propyl-1,2-benzisothiazol-3(2H)-one1,1-Dioxide Fumarate

M.p.: 186°-187° C., IR (KBr) cm⁻¹ : 3400, 1720, 1710, 1600, 1505, 1460,1330, 1300, 1250, 1220, 1180, 1160, 920, 840, 780, 750, 670, 630, 580,510. ¹ H-NMR (CD₃ OD) δ: 2.5-2.6 (2H, m), 2.7-3.2 (1OH, m), 5.37 (1H,dd, J=6 Hz, 9 Hz), 6.72 (2H, s), 7.1-8.1 (8H, m).

In the following Examples XXIX to XXXI, the compounds were preparedessentially in the same manner as in Example I. The prepared compoundsand characteristics thereof are set forth below.

Example XXIX2-(3-Dimethylamino-1-phenyl)propyl-1,2-benzisothiazol-3(2H)-one1,1-Dioxide Fumarate

M.p.: 170°-173° C., IR (KBr) cm⁻¹ : 3410, 2940, 2660, 1720, 1680, 1610,1455, 1325, 1290, 1250, 1180, 980, 745, 640, 580. ¹ H-NMR (CD₃ OD) δ:2.86 (6H, s), 2.4-3.4 (4H, m), 5.2-5.5 (1H, m), 6.68 (2H, s), 7.1-8.1(9H, m).

Example XXX2-(3-Diethylamino-1-phenyl)propyl-1,2-benzisothiazol-3(2H)-one1,1-Dioxide Fumarate

M.p.: 173°-176° C., IR (KBr) cm⁻¹ : 3430, 1730, 1330, 1295, 1260, 1185,990. ¹ H-NMR (D₂ O) δ: 1.27 (6H, t, J=7 Hz), 2.6-3.4 (4H, m), 3.26 (4H,q, J=7 Hz), 5.50 (1H, t, J=8 Hz), 6.65 (2H, s), 7.4-8.1 (9H, m).

Example XXXI2-(3-Benzylethylamino-1-phenyl)propyl-1,2-benzisothiazol-3(2H)-one1,1-Dioxide Fumarate

Amorphous

IR (KBr) cm⁻¹ : 3400, 1720, 1450, 1370, 1330, 1285, 1245, 1180, 970,740, 690, 580. ¹ H-NMR (CD₃ OD) δ: 1.31 (3H, t, J=8 Hz), 2.5-3.3 (6H,m), 4.28 (2H, s), 5.1-5.4 (1H, m), 6.70 (2H, s), 7.2-7.6 (12H, m, ArH),7.8-8.1 (2H, m).

Example XXXII2-(3-Morpholino-1-phenyl)propyl-1,2-benzisothiazol-3(2H)-one 1-OxideFumarate (1)2-(3-Morpholino-1-phenyl)propyl-1,2-benzisothiazol-3(2H)-one 1-Oxide

In DMF (2 mL) were suspended 4- (3-chloro-3-phenyl)propyl!morpholinehydrochloride (116 mg, 0.42 mmol.), 1,2-benzisothiazol-3(2H)-one 1-oxide(70 mg, 0.42 mmol.), and cesium carbonate (137 mg, 0.42 mmol.). Thesuspension was stirred at room temperature for 70 hours to carry out areaction. The reaction liquid was placed under reduced pressure todistill DMF off. To the residue were added water and ethyl acetate, andthe organic layer was taken out. The organic portion was washed with anaqueous saturated sodium chloride solution, dried over anhydrous sodiumsulfate, and placed under reduced pressure to distill the solvent off.The residue was subjected to silica gel column chromatography(chloroform/methanol=100/1) to obtain 19 mg of the desired compound(yield 12%) as a colorless oil.

¹ H-NMR (CDCl₃) δ: 2.3-2.8 (8H, m), 3.6-3.8 (4H, m), 5.76 (1H, t, J=8Hz), 7.3-7.4 (3H, m), 7.5-7.6 (2H, m), 7.7-7.8 (3H, m), 7.97 (1H, dd,J=7 Hz, 1 Hz).

(2) 2-(3-Morpholino-1-phenyl)propyl-1,2-benzisothiazol-3(2H)-one 1-OxideFumarate

A solution of fumaric acid (6 mg) in hot ethanol (6 mL) was added to asolution of 2-(3-morpholino-1-phenyl)propyl-1,2-benzisothiazol-3(2H)-one1-oxide (19 mg) in ethanol (2 mL). The mixture was concentrated underreduced pressure to approx. 1 mL, and then allowed to stand two days atroom temperature. Insolubles precipitated and were collected byfiltration. The collected insolubles were washed successively withethanol and hexane, to give 15 mg of the desired compound (yield 61%) asa white crystalline product.

IR (KBr) cm⁻¹ : 3420, 1700, 1620, 1460, 1300, 1240, 1120. ¹ H-NMR (D₂ O)δ: 2.7-4.2 (12H, m), 5.72 (1H, t, J=8 Hz), 6.65 (2H, s), 7.4-7.6 (5H,m), 7.8-8.0 (3H, m), 8.04 (1H, d, J=7 Hz).

Example XXXIII 2-(3-Piperidino-1-phenyl)propyl-1,2-benzisothiazoline1,1-Dioxide Fumarate (1)2-(3-Piperidino-1-phenyl)propyl-1,2-benzisothiazoline 1,1-Dioxide

In anhydrous ethanol was dissolved sodium (131 mg, 5.7 mmol.). To theobtained solution were added 1,2-benzisothiazoline (483 mg, 2.85 mmol.)and 1-((3-chloro-3-phenyl)propyl!piperidine hydrochloride (783 mg, 2.85mmol). The mixture was then heated for 7 hours under refluxing. Thereaction liquid was placed under reduced pressure to distill the solventoff. To the residue were added water and ethyl acetate, and the organiclayer was taken out. The organic portion was washed with an aqueoussaturated sodium chloride solution, dried over anhydrous sodium sulfate,and placed under reduced pressure. The residue was subjected to silicagel column chromatography (chloroform/methanol=40/1) to give 890 mg ofthe desired compound (yield 84%) as a white crystalline product.

M.p.: 117°-118° C., IR (KBr) cm⁻¹ : 2920, 2800, 1450, 1280, 1210, 1170,1150, 1120, 1060, 1040, 800, 760, 745, 720, 700, 560. ¹ H-NMR (CDCl₃) δ:1.0-1.8 (6H, m), 1.9-2.6 (8H, m), 3.95 (1H, d, J=14 Hz), 4.30 (1H, d,J=14 Hz), 4.95 (1H, t, J=7 Hz), 7.1-7.9 (9H, m).

(2) 2-(3-Piperidino-1-phenyl)propyl-1,2-benzisothiazoline 1,1-DioxideFumarate

A solution of fumaric acid (130 mg, 1.12 mmol.) in hot ethanol (13 mL)was added to a solution of2-(3-piperidino-1-phenyl)propyl-1,2-benzisothiazoline 1,1-dioxide (415mg, 1.12 mmol.) in ethanol (20 mL). The mixture was allowed to standovenight at room temperature. Insolubles precipitated and were collectedby filtration. The collected insolubles were washed successively withethanol and hexane, to give 430 mg of the desired compound (yield 79%)as a white crystalline product.

M.p.: 205°-206° C. (decomp.), IR (KBr) cm⁻¹ : 3420, 2930, 1720, 1640,1600, 1450, 1285, 1170, 1160, 1120, 980, 755, 630. ¹ H-NMR (DMSO-d₆) δ:1.2-1.8 (6H, m), 2.1-2.9 (8H, m), 4.02 (1H, d, J=14 Hz), 4.50 (1H, d,J=14 Hz), 4.91 (1H, t, J=7 Hz), 6.54 (2H, s), 7.1-7.9 (9H, m).

Example XXXIV 2-(3-Morpholino-1-phenyl)propyl-1,2-benzisothiazoline1,1-Dioxide Fumarate

This was prepared essentially in the same manner as in Example XXXIII.

M.p.: 191°-192° C., IR (KBr) cm⁻¹ : 3420, 1710, 1450, 1310, 1280, 1170,1150, 1120, 980, 765, 630. ¹ H-NMR (DMSO-d₆) δ: 2.0-2.6 (8H, m), 3.3-3.7(4H, m), 4.02 (1H, d, J=15 Hz), 4.47 (1H, d, J=15 Hz), 4.91 (1H, t, J=7Hz), 6.61 (2H, s), 7.1-7.9 (9H, m).

INDUSTRIAL APPLICABILITY

The alkylenediamine derivative of the invention and itspharmacologically acceptable salt can relieve urinating contractionwhich is observed under high intracystic pressure, and can be used fortreating nervous dysuria, chronic prostatitis, chronic cystitis, dysuriacaused by neurogenic bladder or unstable bladder, incontinence of urine,urgency of micturition, and residual urine, and therefore is of value asan active ingredient of a therapeutic agent for treating dysuria.

We claim:
 1. An alkylenediamine derivative having the formula ##STR29##in which R¹ represents an atom or a group selected from the groupconsisting of hydrogen, alkyl having 1-8 carbon atoms, halogen,haloalkyl having 1-4 carbon atoms, hydroxyl, alkoxy having 1-8 having1-8 carbon atoms, aryloxy having 4-10 carbon atoms, aralkyloxy having5-14 carbon atoms, its alkyl portion having 1-4 carbon atoms, nitro,amino, cyano, alkylamino having 1-8 carbon atoms, aralkylamino having5-14 carbon atoms, its alkyl portion having 1-4 carbon atoms, arylaminohaving 4-10 carbon atoms, aliphatic acylamino having 1-8 carbon atoms,carboxyl, alkoxycarbonyl having 2-9 carbon atoms, aralkyloxycarbonylhaving 6-15 carbon atoms, its alkyl portion having 1-4 carbon atoms,aryloxycarbonyl having 5-11 carbon atoms, carbamoyl, sulfo,alkoxysulfonyl having 1-8 carbon atoms, aralkyloxysulfonyl having 5-14carbon atoms, its alkyl portion having 1-4 carbon atoms, aryloxysulfonylhaving 4-10 carbon atoms, sulfonamide, and 1H-tetrazol-5-yl;R²represents an aryl group having 4-10 carbon atoms, aralkyl group having5-14 carbon atoms, its alkyl portion having 1-4 carbon atoms, or anaromatic heterocyclic group each of which may have one to five same ordifferent substituents selected from the group consisting of alkylhaving 1-8 carbon atoms, halogen, haloalkyl having 1-4 carbon atoms,hydroxyl, alkoxy having 1-8 carbon atoms, aryloxy having 4-10 carbonatoms, aralkyloxy having 5-14 carbon atoms, its alkyl portion having 1-4carbon atoms, nitro, amino, cyano, alkylamino having 1-8 carbon atoms,aralkylamino having 5-14 carbon atoms, its alkylportion having 1-4carbon atoms, arylamino having 4-10 carbon atoms, aliphatic acylaminohaving 1-8 carbon atoms, carboxyl, alkoxycarbonyl having 2-9 carbonatoms, aralkyloxycarbonyl having 6-15 carbon atoms, its alkyl portionhaving 1-4 carbon atoms, aryloxycarbonyl having 5-11 carbon atoms,carbamoyl, sulfo, alkoxysulfonyl having 1-8 carbon atoms,aralkyloxysulfonyl having 5-14 carbon atoms, its alkyl portion having1-4 carbon atoms, aryloxysulfonyl having 4-10 carbon atoms, sulfonamideand 1H-tetrazol-5-yl; each of R³ and R⁴ independently representshydrogen, alkyl having 1-8 carbon atoms, aralkyl having 5-14 carbonatoms, its alkyl portion having 1-4 carbon atoms, or aryl having 4-10carbon atoms, or R³ and R⁴ form in combination with the nitrogen atom towhich R³ and R⁴ are attached, a hetero ring which may contain anothernitrogen, oxygen or sulfur as the ring-forming atom in addition to theformer nitrogen atom and which may have a substituent selected from thegroup consisting of alkyl having 1-8 carbon atoms which may have one ortwo aryl having 4-10 carbon atoms as substituent, phenyl, hydroxyl,alkoxy having 1-8 carbon atoms, which may have one or two aryl having4-10 carbon atoms as substituent, aryloxy having 4-10 carbon atoms,carboxyl and cyano, provided that where R² is phenyl, R³ and R⁴ cannotboth be hydrogen; k is an integer of 1 to 4; each of m and nindependently represents an integer of 0-4, under the condition that thetotal number of m and n is in the range of 0-4; p is 0, l or 2; q is 0or 1; and each of w, x, y and z independently is an integer of 0 to 1,under the condition that the total number of w, x, y and z is
 1. 2. Thealkylenediamine derivative of claim 1, which is represented by theformula (2): ##STR30## in which R¹, R², R³, R⁴, k, m, and n are the sameas those defined in claim
 1. 3. The alkylenediamine derivative of claim1 which is represented by the formula (3): ##STR31## in which R¹, R²,R³, R⁴, k, m, and n are the same as those defined in claim
 1. 4. Atherapeutic agent for treatment of dysuria comprising a carrier and analkylenediamine derivative having the formula ##STR32## in which R¹represents an atom or a group selected from the group consisting ofhydrogen, alkyl having 1-8 carbon atoms, halogen, haloalkyl having 1-4carbon atoms, hydroxyl, alkoxy having 1-8 having 1-8 carbon atoms,aryloxy having 4-10 carbon atoms, aralkyloxy having 5-14 carbon atoms,its alkyl portion having 1-4 carbon atoms, nitro, amino, cyano,alkylamino having 1-8 carbon atoms, aralkylamino having 5-14 carbonatoms, its alkyl portion having 1-4 carbon atoms, arylamino having 4-10carbon atoms, aliphatic acylamino having 1-8 carbon atoms, carboxyl,alkoxycarbonyl having 2-9 carbon atoms, aralkyloxycarbonyl having 6-15carbon atoms, its alkyl portion having 1-4 carbon atoms, aryloxycarbonylhaving 5-11 carbon atoms, carbamoyl, sulfo, alkoxysulfonyl having 1-8carbon atoms, aralkyloxysulfonyl having 5-14 carbon atoms, its alkylportion having 1-4 carbon atoms, aryloxysulfonyl having 4-10 carbonatoms, sulfonamide, and 1H-tetrazol-5-yl;R² represents hydrogen, alkylhaving 1-8 carbon atoms, alkenyl having 2-9 carbon atoms, alkoxy having1-8 carbon atoms, or an aryl having 4-10 carbon atoms, aralkyl having5-14 carbon atoms, its alkyl portion having 1-4 carbon atoms, or anaromatic heterocyclic group which may have one to five same or differentsubstituents selected from the group consisting of alkyl having 1-8carbon atoms, halogen, haloalkyl having 1-4 carbon atoms, hydroxyl,alkoxy having 1-8 carbon atoms, aryloxy having 4-10 carbon atoms,aralkyloxy having 5-14 carbon atoms, its alkyl portion having 1-4 carbonatoms, nitro, amino, cyano, alkylamino having 1-8 carbon atoms,aralkylamino having 5-14 carbon atoms, its alkyl portion having 1-4carbon atoms, arylamino having 4-10 carbon atoms, aliphatic acylaminohaving 1-8 carbon atoms, carboxyl, alkoxycarbonyl having 2-9 carbonatoms, aralkyloxycarbonyl having 6-15 carbon atoms, its alkyl portionhaving 1-4 carbon atoms, aryloxycarbonyl having 5-11 carbon atoms,carbamoyl, sulfo, alkoxysulfonyl having 1-8 carbon atoms,aralkyloxysulfonyl having 5-14 carbon atoms, its alkyl portion having1-4 carbon atoms, aryloxysulfonyl having 4-10 carbon atoms, sulfonamideand 1H-tetrazol-5-yl; each of R³ and R⁴ independently representshydrogen, alkyl having 1-8 carbon atoms, aralkyl having 5-14 carbonatoms, its alkyl portion having 1-4 carbon atoms, or aryl having 4-10carbon atoms, or R³ and R⁴ form in combination with the nitrogen atom towhich R³ and R⁴ are attached, a hetero ring which may contain anothernitrogen, oxygen or sulfur as the ring-forming atom in addition to theformer nitrogen atom and which may have a substituent selected from thegroup consisting of alkyl having 1-8 carbon atoms which may have one ortwo aryl having 4-10 carbon atoms as substituent, phenyl, hydroxyl,alkoxy having 1-8 carbon atoms which may have one or two aryl having4-10 carbon atoms as substituent, aryloxy having 4-10 carbon atoms,carboxyl and cyano, provided that where R² is hydrogen, R³ and R⁴ formin combination with the nitrogen atom to which R³ and R⁴ are attached, ahetero ring which may contain another nitrogen, oxygen or sulfur as thering-forming atom in addition to the former nitrogen atom and which hasa substituent selected from the group consisting of alkyl having 1-8carbon atoms which may have one or two aryl having 4-10 carbon atoms assubstituent, phenyl, hydroxyl, alkoxy having 1-8 carbon atoms which mayhave one or two aryl having 4-10 carbon atoms, carboxyl and cyano, andwhere R² is alkyl or phenyl, R³ and R⁴ cannot both be hydrogen; k is aninteger of 1 to 4; each of m and n independently represents an integerof 0 to 4, under the condition that the total number of m and n is inthe range of 0 to 4; p is 0, 1 or 2; q is 0 or 1; and each of w, x, yand z independently is an integer of 0 to 1, under the condition thatthe total number of w, x, y and z is 1.